EP3359209B1 - Zusammensetzungen und verfahren zur behandlung von knochendefekten - Google Patents
Zusammensetzungen und verfahren zur behandlung von knochendefekten Download PDFInfo
- Publication number
- EP3359209B1 EP3359209B1 EP16788416.2A EP16788416A EP3359209B1 EP 3359209 B1 EP3359209 B1 EP 3359209B1 EP 16788416 A EP16788416 A EP 16788416A EP 3359209 B1 EP3359209 B1 EP 3359209B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- bone
- composition
- reconstruction
- biocompatible matrix
- biocompatible
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 210000000988 bone and bone Anatomy 0.000 title claims description 408
- 239000000203 mixture Substances 0.000 title claims description 192
- 230000007547 defect Effects 0.000 title claims description 105
- 238000011282 treatment Methods 0.000 title claims description 56
- 238000000034 method Methods 0.000 title description 56
- 239000012867 bioactive agent Substances 0.000 claims description 89
- 239000000463 material Substances 0.000 claims description 87
- 239000011159 matrix material Substances 0.000 claims description 68
- 239000003795 chemical substances by application Substances 0.000 claims description 48
- 229940122361 Bisphosphonate Drugs 0.000 claims description 45
- 229910052588 hydroxylapatite Inorganic materials 0.000 claims description 44
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 claims description 44
- 150000004663 bisphosphonates Chemical class 0.000 claims description 43
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 43
- 239000002245 particle Substances 0.000 claims description 38
- 159000000007 calcium salts Chemical class 0.000 claims description 31
- 229960000308 fosfomycin Drugs 0.000 claims description 19
- YMDXZJFXQJVXBF-STHAYSLISA-N fosfomycin Chemical compound C[C@@H]1O[C@@H]1P(O)(O)=O YMDXZJFXQJVXBF-STHAYSLISA-N 0.000 claims description 19
- 230000000123 anti-resoprtive effect Effects 0.000 claims description 17
- 239000007787 solid Substances 0.000 claims description 10
- 239000001506 calcium phosphate Substances 0.000 claims description 9
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 9
- 235000011010 calcium phosphates Nutrition 0.000 claims description 9
- 239000004615 ingredient Substances 0.000 claims description 9
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 9
- 210000002805 bone matrix Anatomy 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 150000002632 lipids Chemical class 0.000 claims description 3
- 229920001059 synthetic polymer Polymers 0.000 claims description 3
- 238000000465 moulding Methods 0.000 claims description 2
- 229920005615 natural polymer Polymers 0.000 claims description 2
- 229960004276 zoledronic acid Drugs 0.000 description 34
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 34
- 239000002904 solvent Substances 0.000 description 23
- 230000003115 biocidal effect Effects 0.000 description 21
- 230000012010 growth Effects 0.000 description 21
- 230000011164 ossification Effects 0.000 description 21
- 150000003839 salts Chemical class 0.000 description 21
- 239000006072 paste Substances 0.000 description 20
- 238000002156 mixing Methods 0.000 description 19
- 230000000278 osteoconductive effect Effects 0.000 description 19
- 239000003242 anti bacterial agent Substances 0.000 description 17
- 238000007634 remodeling Methods 0.000 description 17
- 206010028980 Neoplasm Diseases 0.000 description 14
- 239000004599 antimicrobial Substances 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 13
- 230000002980 postoperative effect Effects 0.000 description 13
- 230000001737 promoting effect Effects 0.000 description 12
- 229920000642 polymer Polymers 0.000 description 11
- 229940088710 antibiotic agent Drugs 0.000 description 10
- -1 nitrogen containing bisphosphonate Chemical class 0.000 description 10
- 230000000750 progressive effect Effects 0.000 description 10
- 210000000689 upper leg Anatomy 0.000 description 10
- 206010017076 Fracture Diseases 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- 208000010392 Bone Fractures Diseases 0.000 description 8
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 8
- 229930182566 Gentamicin Natural products 0.000 description 8
- 230000006378 damage Effects 0.000 description 8
- 239000003102 growth factor Substances 0.000 description 8
- 239000007943 implant Substances 0.000 description 8
- 208000015181 infectious disease Diseases 0.000 description 8
- 230000002138 osteoinductive effect Effects 0.000 description 8
- 238000001356 surgical procedure Methods 0.000 description 8
- 239000004606 Fillers/Extenders Substances 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 238000001574 biopsy Methods 0.000 description 7
- 201000011510 cancer Diseases 0.000 description 7
- 239000002131 composite material Substances 0.000 description 7
- 238000011065 in-situ storage Methods 0.000 description 7
- 210000002997 osteoclast Anatomy 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 206010027476 Metastases Diseases 0.000 description 6
- 229920001710 Polyorthoester Polymers 0.000 description 6
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 6
- 208000005250 Spontaneous Fractures Diseases 0.000 description 6
- 239000000654 additive Substances 0.000 description 6
- 201000011143 bone giant cell tumor Diseases 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 230000001054 cortical effect Effects 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000002513 implantation Methods 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 239000004332 silver Substances 0.000 description 6
- 229910052709 silver Inorganic materials 0.000 description 6
- 208000018084 Bone neoplasm Diseases 0.000 description 5
- 206010011732 Cyst Diseases 0.000 description 5
- 208000002966 Giant Cell Tumor of Bone Diseases 0.000 description 5
- 208000037848 Metastatic bone disease Diseases 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 239000002617 bone density conservation agent Substances 0.000 description 5
- 238000002591 computed tomography Methods 0.000 description 5
- 208000031513 cyst Diseases 0.000 description 5
- 238000011049 filling Methods 0.000 description 5
- 230000035876 healing Effects 0.000 description 5
- 230000003116 impacting effect Effects 0.000 description 5
- 230000001394 metastastic effect Effects 0.000 description 5
- 206010061289 metastatic neoplasm Diseases 0.000 description 5
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 4
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 4
- 108010059993 Vancomycin Proteins 0.000 description 4
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 4
- 230000003214 anti-biofilm Effects 0.000 description 4
- 230000000845 anti-microbial effect Effects 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 230000032770 biofilm formation Effects 0.000 description 4
- 201000007327 bone benign neoplasm Diseases 0.000 description 4
- 230000010072 bone remodeling Effects 0.000 description 4
- 238000002725 brachytherapy Methods 0.000 description 4
- 230000006835 compression Effects 0.000 description 4
- 238000007906 compression Methods 0.000 description 4
- 229960002518 gentamicin Drugs 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000005855 radiation Effects 0.000 description 4
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 4
- 210000004872 soft tissue Anatomy 0.000 description 4
- 125000006850 spacer group Chemical group 0.000 description 4
- 241000894007 species Species 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- 229960003165 vancomycin Drugs 0.000 description 4
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 4
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 4
- WZRJTRPJURQBRM-UHFFFAOYSA-N 4-amino-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide;5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1.COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 WZRJTRPJURQBRM-UHFFFAOYSA-N 0.000 description 3
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 3
- 206010061728 Bone lesion Diseases 0.000 description 3
- 229930186147 Cephalosporin Natural products 0.000 description 3
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 description 3
- 102000013275 Somatomedins Human genes 0.000 description 3
- 239000004098 Tetracycline Substances 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 229960004343 alendronic acid Drugs 0.000 description 3
- 150000001412 amines Chemical group 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 230000000975 bioactive effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 230000008468 bone growth Effects 0.000 description 3
- 239000006285 cell suspension Substances 0.000 description 3
- 229940124587 cephalosporin Drugs 0.000 description 3
- 150000001780 cephalosporins Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 238000007596 consolidation process Methods 0.000 description 3
- 238000002316 cosmetic surgery Methods 0.000 description 3
- 239000000824 cytostatic agent Substances 0.000 description 3
- 230000004069 differentiation Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 210000002758 humerus Anatomy 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 230000000813 microbial effect Effects 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 210000000963 osteoblast Anatomy 0.000 description 3
- 239000004926 polymethyl methacrylate Substances 0.000 description 3
- 229960000759 risedronic acid Drugs 0.000 description 3
- 230000011664 signaling Effects 0.000 description 3
- 230000003319 supportive effect Effects 0.000 description 3
- 235000019364 tetracycline Nutrition 0.000 description 3
- 150000003522 tetracyclines Chemical class 0.000 description 3
- 230000008733 trauma Effects 0.000 description 3
- 239000011800 void material Substances 0.000 description 3
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 description 2
- VNTJGCYVIRTGMZ-PXGLAOGESA-N 2-[[2-[[(2s)-2-[[2-[[(2s)-2-[[(2s)-2-[[(2s,3r)-2-[[(2s)-2-[[2-[[(2s)-5-amino-2-[[(2s)-2-[[(2s)-6-amino-2-[[(2s)-2-[[(2s)-2-aminopropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-oxopentanoyl]amino]acety Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](C)N)CC(C)C)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC(=O)NCC(O)=O)C1=CC=C(O)C=C1 VNTJGCYVIRTGMZ-PXGLAOGESA-N 0.000 description 2
- 206010065687 Bone loss Diseases 0.000 description 2
- 102100024504 Bone morphogenetic protein 3 Human genes 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920001661 Chitosan Polymers 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 108010092160 Dactinomycin Proteins 0.000 description 2
- 108010013198 Daptomycin Proteins 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 2
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 2
- 101000695367 Homo sapiens Bone morphogenetic protein 10 Proteins 0.000 description 2
- 101000695360 Homo sapiens Bone morphogenetic protein 15 Proteins 0.000 description 2
- 101000762366 Homo sapiens Bone morphogenetic protein 2 Proteins 0.000 description 2
- 101000762375 Homo sapiens Bone morphogenetic protein 3 Proteins 0.000 description 2
- 101000762379 Homo sapiens Bone morphogenetic protein 4 Proteins 0.000 description 2
- 101000899388 Homo sapiens Bone morphogenetic protein 5 Proteins 0.000 description 2
- 101000899390 Homo sapiens Bone morphogenetic protein 6 Proteins 0.000 description 2
- 101000899361 Homo sapiens Bone morphogenetic protein 7 Proteins 0.000 description 2
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 2
- 102000000589 Interleukin-1 Human genes 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 101800003595 Osteogenic growth peptide Proteins 0.000 description 2
- 208000003076 Osteolysis Diseases 0.000 description 2
- 102000043299 Parathyroid hormone-related Human genes 0.000 description 2
- 101710123753 Parathyroid hormone-related protein Proteins 0.000 description 2
- 206010034156 Pathological fracture Diseases 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 2
- 229920002732 Polyanhydride Polymers 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 102000014128 RANK Ligand Human genes 0.000 description 2
- 108010025832 RANK Ligand Proteins 0.000 description 2
- 102000019307 Sclerostin Human genes 0.000 description 2
- 108050006698 Sclerostin Proteins 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- 208000009443 Vascular Malformations Diseases 0.000 description 2
- UGEPSJNLORCRBO-UHFFFAOYSA-N [3-(dimethylamino)-1-hydroxy-1-phosphonopropyl]phosphonic acid Chemical compound CN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O UGEPSJNLORCRBO-UHFFFAOYSA-N 0.000 description 2
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000000340 anti-metabolite Effects 0.000 description 2
- 229940100197 antimetabolite Drugs 0.000 description 2
- 239000002256 antimetabolite Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012620 biological material Substances 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 210000000845 cartilage Anatomy 0.000 description 2
- XIURVHNZVLADCM-IUODEOHRSA-N cefalotin Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C(O)=O)C(=O)CC1=CC=CS1 XIURVHNZVLADCM-IUODEOHRSA-N 0.000 description 2
- 239000004568 cement Substances 0.000 description 2
- JQXXHWHPUNPDRT-BQVAUQFYSA-N chembl1523493 Chemical compound O([C@](C1=O)(C)O\C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)/C=C\C=C(C)/C(=O)NC=2C(O)=C3C(O)=C4C)C)OC)C4=C1C3=C(O)C=2C=NN1CCN(C)CC1 JQXXHWHPUNPDRT-BQVAUQFYSA-N 0.000 description 2
- 102000006533 chordin Human genes 0.000 description 2
- 108010008846 chordin Proteins 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 229940047766 co-trimoxazole Drugs 0.000 description 2
- 239000002872 contrast media Substances 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 229960000640 dactinomycin Drugs 0.000 description 2
- 229960005484 daptomycin Drugs 0.000 description 2
- DOAKLVKFURWEDJ-QCMAZARJSA-N daptomycin Chemical compound C([C@H]1C(=O)O[C@H](C)[C@@H](C(NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@H](C(=O)N1)[C@H](C)CC(O)=O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCCCCCCCC)C(=O)C1=CC=CC=C1N DOAKLVKFURWEDJ-QCMAZARJSA-N 0.000 description 2
- 239000010432 diamond Substances 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 description 2
- 210000002436 femur neck Anatomy 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 239000000122 growth hormone Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 229960005236 ibandronic acid Drugs 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 229940100601 interleukin-6 Drugs 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 208000029791 lytic metastatic bone lesion Diseases 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 210000002901 mesenchymal stem cell Anatomy 0.000 description 2
- 239000013528 metallic particle Substances 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 229960004023 minocycline Drugs 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 230000000921 morphogenic effect Effects 0.000 description 2
- PUUSSSIBPPTKTP-UHFFFAOYSA-N neridronic acid Chemical compound NCCCCCC(O)(P(O)(O)=O)P(O)(O)=O PUUSSSIBPPTKTP-UHFFFAOYSA-N 0.000 description 2
- 229950010733 neridronic acid Drugs 0.000 description 2
- 108700007229 noggin Proteins 0.000 description 2
- 102000045246 noggin Human genes 0.000 description 2
- 229950004969 olpadronic acid Drugs 0.000 description 2
- 230000001582 osteoblastic effect Effects 0.000 description 2
- 230000002642 osteogeneic effect Effects 0.000 description 2
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 2
- 229960003978 pamidronic acid Drugs 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 229940056360 penicillin g Drugs 0.000 description 2
- 201000001245 periodontitis Diseases 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 210000004623 platelet-rich plasma Anatomy 0.000 description 2
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000012857 radioactive material Substances 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- 238000002271 resection Methods 0.000 description 2
- 229960001225 rifampicin Drugs 0.000 description 2
- 102000034285 signal transducing proteins Human genes 0.000 description 2
- 108091006024 signal transducing proteins Proteins 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- 229960002180 tetracycline Drugs 0.000 description 2
- 229930101283 tetracycline Natural products 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 210000002303 tibia Anatomy 0.000 description 2
- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 description 2
- 229960004659 ticarcillin Drugs 0.000 description 2
- 239000010936 titanium Substances 0.000 description 2
- 229910052719 titanium Inorganic materials 0.000 description 2
- 229960000707 tobramycin Drugs 0.000 description 2
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 2
- 239000000606 toothpaste Substances 0.000 description 2
- 229940034610 toothpaste Drugs 0.000 description 2
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- CIDUJQMULVCIBT-MQDUPKMGSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4-amino-3-[[(2s,3r)-3-amino-6-(aminomethyl)-3,4-dihydro-2h-pyran-2-yl]oxy]-6-(ethylamino)-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](NC)[C@@](C)(O)CO1)O)NCC)[C@H]1OC(CN)=CC[C@H]1N CIDUJQMULVCIBT-MQDUPKMGSA-N 0.000 description 1
- LITBAYYWXZOHAW-XDZRHBBOSA-N (2s,5r,6r)-6-[[(2r)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;(2s,3s,5r)-3-methyl-4,4,7-trioxo-3-(triazol-1-ylmethyl)-4$l^{6}-thia-1-azabicyclo[3.2.0]hept Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1.O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 LITBAYYWXZOHAW-XDZRHBBOSA-N 0.000 description 1
- VCOPTHOUUNAYKQ-WBTCAYNUSA-N (3s)-3,6-diamino-n-[[(2s,5s,8e,11s,15s)-15-amino-11-[(6r)-2-amino-1,4,5,6-tetrahydropyrimidin-6-yl]-8-[(carbamoylamino)methylidene]-2-(hydroxymethyl)-3,6,9,12,16-pentaoxo-1,4,7,10,13-pentazacyclohexadec-5-yl]methyl]hexanamide;(3s)-3,6-diamino-n-[[(2s,5s,8 Chemical compound N1C(=O)\C(=C/NC(N)=O)NC(=O)[C@H](CNC(=O)C[C@@H](N)CCCN)NC(=O)[C@H](C)NC(=O)[C@@H](N)CNC(=O)[C@@H]1[C@@H]1NC(N)=NCC1.N1C(=O)\C(=C/NC(N)=O)NC(=O)[C@H](CNC(=O)C[C@@H](N)CCCN)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CNC(=O)[C@@H]1[C@@H]1NC(N)=NCC1 VCOPTHOUUNAYKQ-WBTCAYNUSA-N 0.000 description 1
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 1
- PUDHBTGHUJUUFI-SCTWWAJVSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-p Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 PUDHBTGHUJUUFI-SCTWWAJVSA-N 0.000 description 1
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 1
- SOVUOXKZCCAWOJ-HJYUBDRYSA-N (4s,4as,5ar,12ar)-9-[[2-(tert-butylamino)acetyl]amino]-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=C(NC(=O)CNC(C)(C)C)C(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O SOVUOXKZCCAWOJ-HJYUBDRYSA-N 0.000 description 1
- YCIHPQHVWDULOY-FMZCEJRJSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O YCIHPQHVWDULOY-FMZCEJRJSA-N 0.000 description 1
- GUXHBMASAHGULD-SEYHBJAFSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1([C@H]2O)=C(Cl)C=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O GUXHBMASAHGULD-SEYHBJAFSA-N 0.000 description 1
- HBUJYEUPIIJJOS-PBHICJAKSA-N (5r)-3-[4-[1-[(2s)-2,3-dihydroxypropanoyl]-3,6-dihydro-2h-pyridin-4-yl]-3,5-difluorophenyl]-5-(1,2-oxazol-3-yloxymethyl)-1,3-oxazolidin-2-one Chemical compound C1N(C(=O)[C@@H](O)CO)CCC(C=2C(=CC(=CC=2F)N2C(O[C@@H](COC3=NOC=C3)C2)=O)F)=C1 HBUJYEUPIIJJOS-PBHICJAKSA-N 0.000 description 1
- WDLWHQDACQUCJR-ZAMMOSSLSA-N (6r,7r)-7-[[(2r)-2-azaniumyl-2-(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-[(e)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)/C=C/C)C(O)=O)=CC=C(O)C=C1 WDLWHQDACQUCJR-ZAMMOSSLSA-N 0.000 description 1
- MMRINLZOZVAPDZ-LSGRDSQZSA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(1-methylpyrrolidin-1-ium-1-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;chloride Chemical compound Cl.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 MMRINLZOZVAPDZ-LSGRDSQZSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- MINDHVHHQZYEEK-UHFFFAOYSA-N (E)-(2S,3R,4R,5S)-5-[(2S,3S,4S,5S)-2,3-epoxy-5-hydroxy-4-methylhexyl]tetrahydro-3,4-dihydroxy-(beta)-methyl-2H-pyran-2-crotonic acid ester with 9-hydroxynonanoic acid Natural products CC(O)C(C)C1OC1CC1C(O)C(O)C(CC(C)=CC(=O)OCCCCCCCCC(O)=O)OC1 MINDHVHHQZYEEK-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- RXZBMPWDPOLZGW-XMRMVWPWSA-N (E)-roxithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N/OCOCCOC)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 RXZBMPWDPOLZGW-XMRMVWPWSA-N 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 description 1
- NCCJWSXETVVUHK-ZYSAIPPVSA-N (z)-7-[(2r)-2-amino-2-carboxyethyl]sulfanyl-2-[[(1s)-2,2-dimethylcyclopropanecarbonyl]amino]hept-2-enoic acid;(5r,6s)-3-[2-(aminomethylideneamino)ethylsulfanyl]-6-[(1r)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound C1C(SCC\N=C/N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21.CC1(C)C[C@@H]1C(=O)N\C(=C/CCCCSC[C@H](N)C(O)=O)C(O)=O NCCJWSXETVVUHK-ZYSAIPPVSA-N 0.000 description 1
- ACTOXUHEUCPTEW-BWHGAVFKSA-N 2-[(4r,5s,6s,7r,9r,10r,11e,13e,16r)-6-[(2s,3r,4r,5s,6r)-5-[(2s,4r,5s,6s)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-10-[(2s,5s,6r)-5-(dimethylamino)-6-methyloxan-2-yl]oxy-4-hydroxy-5-methoxy-9,16-dimethyl-2-o Chemical compound O([C@H]1/C=C/C=C/C[C@@H](C)OC(=O)C[C@@H](O)[C@@H]([C@H]([C@@H](CC=O)C[C@H]1C)O[C@H]1[C@@H]([C@H]([C@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](C)(O)C2)[C@@H](C)O1)N(C)C)O)OC)[C@@H]1CC[C@H](N(C)C)[C@@H](C)O1 ACTOXUHEUCPTEW-BWHGAVFKSA-N 0.000 description 1
- WZPBZJONDBGPKJ-VEHQQRBSSA-L 2-[(z)-[1-(2-amino-1,3-thiazol-4-yl)-2-[[(2s,3s)-2-methyl-4-oxo-1-sulfonatoazetidin-3-yl]amino]-2-oxoethylidene]amino]oxy-2-methylpropanoate Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C([O-])=O)\C1=CSC(N)=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-L 0.000 description 1
- FUBFWTUFPGFHOJ-UHFFFAOYSA-N 2-nitrofuran Chemical class [O-][N+](=O)C1=CC=CO1 FUBFWTUFPGFHOJ-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 1
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 description 1
- 206010002961 Aplasia Diseases 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 108010001478 Bacitracin Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108060000903 Beta-catenin Proteins 0.000 description 1
- 102000015735 Beta-catenin Human genes 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 108010049951 Bone Morphogenetic Protein 3 Proteins 0.000 description 1
- 108010049870 Bone Morphogenetic Protein 7 Proteins 0.000 description 1
- 102000008131 Bone Morphogenetic Protein 7 Human genes 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 102000004152 Bone morphogenetic protein 1 Human genes 0.000 description 1
- 108090000654 Bone morphogenetic protein 1 Proteins 0.000 description 1
- 102100028726 Bone morphogenetic protein 10 Human genes 0.000 description 1
- 102100028727 Bone morphogenetic protein 15 Human genes 0.000 description 1
- 102100024506 Bone morphogenetic protein 2 Human genes 0.000 description 1
- 102100024505 Bone morphogenetic protein 4 Human genes 0.000 description 1
- 102100022526 Bone morphogenetic protein 5 Human genes 0.000 description 1
- 102100022525 Bone morphogenetic protein 6 Human genes 0.000 description 1
- 102100022544 Bone morphogenetic protein 7 Human genes 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- 108010037003 Buserelin Proteins 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 229910014497 Ca10(PO4)6(OH)2 Inorganic materials 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000004343 Calcium peroxide Substances 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- 108010065839 Capreomycin Proteins 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- GNWUOVJNSFPWDD-XMZRARIVSA-M Cefoxitin sodium Chemical compound [Na+].N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)CC1=CC=CS1 GNWUOVJNSFPWDD-XMZRARIVSA-M 0.000 description 1
- JFPVXVDWJQMJEE-QMTHXVAHSA-N Cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)C(=NOC)C1=CC=CO1 JFPVXVDWJQMJEE-QMTHXVAHSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 1
- GUTLYIVDDKVIGB-OUBTZVSYSA-N Cobalt-60 Chemical compound [60Co] GUTLYIVDDKVIGB-OUBTZVSYSA-N 0.000 description 1
- 108010078777 Colistin Proteins 0.000 description 1
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 1
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- DYDCUQKUCUHJBH-UWTATZPHSA-N D-Cycloserine Chemical compound N[C@@H]1CONC1=O DYDCUQKUCUHJBH-UWTATZPHSA-N 0.000 description 1
- DYDCUQKUCUHJBH-UHFFFAOYSA-N D-Cycloserine Natural products NC1CONC1=O DYDCUQKUCUHJBH-UHFFFAOYSA-N 0.000 description 1
- 108091065053 DAN family Proteins 0.000 description 1
- 102000038900 DAN family Human genes 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- MQJKPEGWNLWLTK-UHFFFAOYSA-N Dapsone Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=C1 MQJKPEGWNLWLTK-UHFFFAOYSA-N 0.000 description 1
- FMTDIUIBLCQGJB-UHFFFAOYSA-N Demethylchlortetracyclin Natural products C1C2C(O)C3=C(Cl)C=CC(O)=C3C(=O)C2=C(O)C2(O)C1C(N(C)C)C(O)=C(C(N)=O)C2=O FMTDIUIBLCQGJB-UHFFFAOYSA-N 0.000 description 1
- 206010058314 Dysplasia Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108010067770 Endopeptidase K Proteins 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- UIOFUWFRIANQPC-JKIFEVAISA-N Floxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl UIOFUWFRIANQPC-JKIFEVAISA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- IECPWNUMDGFDKC-UHFFFAOYSA-N Fusicsaeure Natural products C12C(O)CC3C(=C(CCC=C(C)C)C(O)=O)C(OC(C)=O)CC3(C)C1(C)CCC1C2(C)CCC(O)C1C IECPWNUMDGFDKC-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- JRZJKWGQFNTSRN-UHFFFAOYSA-N Geldanamycin Natural products C1C(C)CC(OC)C(O)C(C)C=C(C)C(OC(N)=O)C(OC)CCC=C(C)C(=O)NC2=CC(=O)C(OC)=C1C2=O JRZJKWGQFNTSRN-UHFFFAOYSA-N 0.000 description 1
- 208000007569 Giant Cell Tumors Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- 108060003393 Granulin Proteins 0.000 description 1
- 206010018852 Haematoma Diseases 0.000 description 1
- 108090000031 Hedgehog Proteins Proteins 0.000 description 1
- 102000003693 Hedgehog Proteins Human genes 0.000 description 1
- 101000912247 Homo sapiens Beta-defensin 103 Proteins 0.000 description 1
- 101000695352 Homo sapiens Bone morphogenetic protein 1 Proteins 0.000 description 1
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 1
- 206010020649 Hyperkeratosis Diseases 0.000 description 1
- 102000002177 Hypoxia-inducible factor-1 alpha Human genes 0.000 description 1
- 108050009527 Hypoxia-inducible factor-1 alpha Proteins 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 206010061217 Infestation Diseases 0.000 description 1
- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical compound O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)NC1=CC=CC(C(O)=O)=C1 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 description 1
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 101150032862 LEF-1 gene Proteins 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 1
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Natural products CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 description 1
- 108010028921 Lipopeptides Proteins 0.000 description 1
- 108090001093 Lymphoid enhancer-binding factor 1 Proteins 0.000 description 1
- 102000004857 Lymphoid enhancer-binding factor 1 Human genes 0.000 description 1
- TYMRLRRVMHJFTF-UHFFFAOYSA-N Mafenide Chemical compound NCC1=CC=C(S(N)(=O)=O)C=C1 TYMRLRRVMHJFTF-UHFFFAOYSA-N 0.000 description 1
- XOGTZOOQQBDUSI-UHFFFAOYSA-M Mesna Chemical compound [Na+].[O-]S(=O)(=O)CCS XOGTZOOQQBDUSI-UHFFFAOYSA-M 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 108010016076 Octreotide Proteins 0.000 description 1
- 206010073853 Osteochondral fracture Diseases 0.000 description 1
- 201000009859 Osteochondrosis Diseases 0.000 description 1
- 206010031252 Osteomyelitis Diseases 0.000 description 1
- 239000004100 Oxytetracycline Substances 0.000 description 1
- 102400000050 Oxytocin Human genes 0.000 description 1
- 101800000989 Oxytocin Proteins 0.000 description 1
- XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- UOZODPSAJZTQNH-UHFFFAOYSA-N Paromomycin II Natural products NC1C(O)C(O)C(CN)OC1OC1C(O)C(OC2C(C(N)CC(N)C2O)OC2C(C(O)C(O)C(CO)O2)N)OC1CO UOZODPSAJZTQNH-UHFFFAOYSA-N 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 229930195708 Penicillin V Natural products 0.000 description 1
- 208000006735 Periostitis Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 108010093965 Polymyxin B Proteins 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- HCWPIIXVSYCSAN-IGMARMGPSA-N Radium-226 Chemical compound [226Ra] HCWPIIXVSYCSAN-IGMARMGPSA-N 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000007660 Residual Neoplasm Diseases 0.000 description 1
- 102400000830 Saposin-B Human genes 0.000 description 1
- 101800001697 Saposin-B Proteins 0.000 description 1
- 206010040102 Seroma Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 239000004187 Spiramycin Substances 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- NHUHCSRWZMLRLA-UHFFFAOYSA-N Sulfisoxazole Chemical compound CC1=NOC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1C NHUHCSRWZMLRLA-UHFFFAOYSA-N 0.000 description 1
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 0.000 description 1
- 108010053950 Teicoplanin Proteins 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- HJLSLZFTEKNLFI-UHFFFAOYSA-N Tinidazole Chemical compound CCS(=O)(=O)CCN1C(C)=NC=C1[N+]([O-])=O HJLSLZFTEKNLFI-UHFFFAOYSA-N 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- 101710136279 Transcriptional regulatory protein MucR Proteins 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 108050003627 Wnt Proteins 0.000 description 1
- 102000013814 Wnt Human genes 0.000 description 1
- ZWBTYMGEBZUQTK-PVLSIAFMSA-N [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,32-tetrahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-1'-(2-methylpropyl)-6,23-dioxospiro[8,33-dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta-1(32),2,4,9,19,21,24,26,30-nonaene-28,4'-piperidine]-13-yl] acetate Chemical compound CO[C@H]1\C=C\O[C@@]2(C)Oc3c(C2=O)c2c4NC5(CCN(CC(C)C)CC5)N=c4c(=NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)c(O)c2c(O)c3C ZWBTYMGEBZUQTK-PVLSIAFMSA-N 0.000 description 1
- 229960000853 abiraterone Drugs 0.000 description 1
- GZOSMCIZMLWJML-VJLLXTKPSA-N abiraterone Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CC[C@H](O)CC3=CC2)C)CC[C@@]11C)C=C1C1=CC=CN=C1 GZOSMCIZMLWJML-VJLLXTKPSA-N 0.000 description 1
- 210000000588 acetabulum Anatomy 0.000 description 1
- 108010052004 acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide Proteins 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 150000003926 acrylamides Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 229960001097 amifostine Drugs 0.000 description 1
- JKOQGQFVAUAYPM-UHFFFAOYSA-N amifostine Chemical compound NCCCNCCSP(O)(O)=O JKOQGQFVAUAYPM-UHFFFAOYSA-N 0.000 description 1
- 229960004821 amikacin Drugs 0.000 description 1
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 1
- 229960003022 amoxicillin Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 229940038195 amoxicillin / clavulanate Drugs 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229940043312 ampicillin / sulbactam Drugs 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 230000000181 anti-adherent effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229910052586 apatite Inorganic materials 0.000 description 1
- 229940003446 arsphenamine Drugs 0.000 description 1
- VLAXZGHHBIJLAD-UHFFFAOYSA-N arsphenamine Chemical compound [Cl-].[Cl-].C1=C(O)C([NH3+])=CC([As]=[As]C=2C=C([NH3+])C(O)=CC=2)=C1 VLAXZGHHBIJLAD-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229960003272 asparaginase Drugs 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 1
- 230000003416 augmentation Effects 0.000 description 1
- 230000003190 augmentative effect Effects 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- 229960003623 azlocillin Drugs 0.000 description 1
- JTWOMNBEOCYFNV-NFFDBFGFSA-N azlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCNC1=O JTWOMNBEOCYFNV-NFFDBFGFSA-N 0.000 description 1
- 229960003644 aztreonam Drugs 0.000 description 1
- 229960003071 bacitracin Drugs 0.000 description 1
- 229930184125 bacitracin Natural products 0.000 description 1
- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-N 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 229960002707 bendamustine Drugs 0.000 description 1
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 description 1
- 238000005452 bending Methods 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229960002938 bexarotene Drugs 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 239000000560 biocompatible material Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000002639 bone cement Substances 0.000 description 1
- 230000037182 bone density Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 229960002719 buserelin Drugs 0.000 description 1
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- PKFDLKSEZWEFGL-MHARETSRSA-N c-di-GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]3[C@@H](O)[C@H](N4C5=C(C(NC(N)=N5)=O)N=C4)O[C@@H]3COP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 PKFDLKSEZWEFGL-MHARETSRSA-N 0.000 description 1
- PPKJUHVNTMYXOD-PZGPJMECSA-N c49ws9n75l Chemical compound O=C([C@@H]1N(C2=O)CC[C@H]1S(=O)(=O)CCN(CC)CC)O[C@H](C(C)C)[C@H](C)\C=C\C(=O)NC\C=C\C(\C)=C\[C@@H](O)CC(=O)CC1=NC2=CO1.N([C@@H]1C(=O)N[C@@H](C(N2CCC[C@H]2C(=O)N(C)[C@@H](CC=2C=CC(=CC=2)N(C)C)C(=O)N2C[C@@H](CS[C@H]3C4CCN(CC4)C3)C(=O)C[C@H]2C(=O)N[C@H](C(=O)O[C@@H]1C)C=1C=CC=CC=1)=O)CC)C(=O)C1=NC=CC=C1O PPKJUHVNTMYXOD-PZGPJMECSA-N 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- 229960004015 calcitonin Drugs 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 description 1
- LHJQIRIGXXHNLA-UHFFFAOYSA-N calcium peroxide Chemical compound [Ca+2].[O-][O-] LHJQIRIGXXHNLA-UHFFFAOYSA-N 0.000 description 1
- 235000019402 calcium peroxide Nutrition 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 229960004602 capreomycin Drugs 0.000 description 1
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 description 1
- 229960003669 carbenicillin Drugs 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 description 1
- 229960005361 cefaclor Drugs 0.000 description 1
- 229960004841 cefadroxil Drugs 0.000 description 1
- NBFNMSULHIODTC-CYJZLJNKSA-N cefadroxil monohydrate Chemical compound O.C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=C(O)C=C1 NBFNMSULHIODTC-CYJZLJNKSA-N 0.000 description 1
- 229960000603 cefalotin Drugs 0.000 description 1
- OLVCFLKTBJRLHI-AXAPSJFSSA-N cefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](O)C=3C=CC=CC=3)[C@H]2SC1 OLVCFLKTBJRLHI-AXAPSJFSSA-N 0.000 description 1
- 229960003012 cefamandole Drugs 0.000 description 1
- 229960001139 cefazolin Drugs 0.000 description 1
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 1
- 229960003719 cefdinir Drugs 0.000 description 1
- RTXOFQZKPXMALH-GHXIOONMSA-N cefdinir Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 RTXOFQZKPXMALH-GHXIOONMSA-N 0.000 description 1
- 229960004069 cefditoren Drugs 0.000 description 1
- KMIPKYQIOVAHOP-YLGJWRNMSA-N cefditoren Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1\C=C/C=1SC=NC=1C KMIPKYQIOVAHOP-YLGJWRNMSA-N 0.000 description 1
- 229960002100 cefepime Drugs 0.000 description 1
- 229960002129 cefixime Drugs 0.000 description 1
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 description 1
- 229960004261 cefotaxime Drugs 0.000 description 1
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 description 1
- 229960002682 cefoxitin Drugs 0.000 description 1
- WYUSVOMTXWRGEK-HBWVYFAYSA-N cefpodoxime Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)C(=O)C(=N/OC)\C1=CSC(N)=N1 WYUSVOMTXWRGEK-HBWVYFAYSA-N 0.000 description 1
- 229960005090 cefpodoxime Drugs 0.000 description 1
- 229960002580 cefprozil Drugs 0.000 description 1
- ZCCUWMICIWSJIX-NQJJCJBVSA-N ceftaroline fosamil Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OCC)C=2N=C(NP(O)(O)=O)SN=2)CC=1SC(SC=1)=NC=1C1=CC=[N+](C)C=C1 ZCCUWMICIWSJIX-NQJJCJBVSA-N 0.000 description 1
- 229960004828 ceftaroline fosamil Drugs 0.000 description 1
- 229960000484 ceftazidime Drugs 0.000 description 1
- NMVPEQXCMGEDNH-TZVUEUGBSA-N ceftazidime pentahydrate Chemical compound O.O.O.O.O.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 NMVPEQXCMGEDNH-TZVUEUGBSA-N 0.000 description 1
- 229960004086 ceftibuten Drugs 0.000 description 1
- UNJFKXSSGBWRBZ-BJCIPQKHSA-N ceftibuten Chemical compound S1C(N)=NC(C(=C\CC(O)=O)\C(=O)N[C@@H]2C(N3C(=CCS[C@@H]32)C(O)=O)=O)=C1 UNJFKXSSGBWRBZ-BJCIPQKHSA-N 0.000 description 1
- 229960001991 ceftizoxime Drugs 0.000 description 1
- NNULBSISHYWZJU-LLKWHZGFSA-N ceftizoxime Chemical compound N([C@@H]1C(N2C(=CCS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 NNULBSISHYWZJU-LLKWHZGFSA-N 0.000 description 1
- VOAZJEPQLGBXGO-SDAWRPRTSA-N ceftobiprole Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(\C=C/4C(N([C@H]5CNCC5)CC\4)=O)CS[C@@H]32)C(O)=O)=O)=N1 VOAZJEPQLGBXGO-SDAWRPRTSA-N 0.000 description 1
- 229950004259 ceftobiprole Drugs 0.000 description 1
- 229960004755 ceftriaxone Drugs 0.000 description 1
- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 description 1
- 229960001668 cefuroxime Drugs 0.000 description 1
- JFPVXVDWJQMJEE-IZRZKJBUSA-N cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 JFPVXVDWJQMJEE-IZRZKJBUSA-N 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229940106164 cephalexin Drugs 0.000 description 1
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- TVFDJXOCXUVLDH-YPZZEJLDSA-N cesium-131 Chemical compound [131Cs] TVFDJXOCXUVLDH-YPZZEJLDSA-N 0.000 description 1
- TVFDJXOCXUVLDH-RNFDNDRNSA-N cesium-137 Chemical compound [137Cs] TVFDJXOCXUVLDH-RNFDNDRNSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- DDTDNCYHLGRFBM-YZEKDTGTSA-N chembl2367892 Chemical compound CC(=O)N[C@H]1[C@@H](O)[C@H](O)[C@H](CO)O[C@H]1O[C@@H]([C@H]1C(N[C@@H](C2=CC(O)=CC(O[C@@H]3[C@H]([C@H](O)[C@H](O)[C@@H](CO)O3)O)=C2C=2C(O)=CC=C(C=2)[C@@H](NC(=O)[C@@H]2NC(=O)[C@@H]3C=4C=C(O)C=C(C=4)OC=4C(O)=CC=C(C=4)[C@@H](N)C(=O)N[C@H](CC=4C=C(Cl)C(O5)=CC=4)C(=O)N3)C(=O)N1)C(O)=O)=O)C(C=C1Cl)=CC=C1OC1=C(O[C@H]3[C@H]([C@@H](O)[C@H](O)[C@H](CO)O3)NC(C)=O)C5=CC2=C1 DDTDNCYHLGRFBM-YZEKDTGTSA-N 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 210000001612 chondrocyte Anatomy 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 229940090805 clavulanate Drugs 0.000 description 1
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 229960002227 clindamycin Drugs 0.000 description 1
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 229960004287 clofazimine Drugs 0.000 description 1
- WDQPAMHFFCXSNU-BGABXYSRSA-N clofazimine Chemical compound C12=CC=CC=C2N=C2C=C(NC=3C=CC(Cl)=CC=3)C(=N/C(C)C)/C=C2N1C1=CC=C(Cl)C=C1 WDQPAMHFFCXSNU-BGABXYSRSA-N 0.000 description 1
- 229960003326 cloxacillin Drugs 0.000 description 1
- LQOLIRLGBULYKD-JKIFEVAISA-N cloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl LQOLIRLGBULYKD-JKIFEVAISA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229960003346 colistin Drugs 0.000 description 1
- 239000000512 collagen gel Substances 0.000 description 1
- 229940047120 colony stimulating factors Drugs 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 230000002153 concerted effect Effects 0.000 description 1
- 108010010201 core binding factor alpha Proteins 0.000 description 1
- 210000005257 cortical tissue Anatomy 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000009109 curative therapy Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960003077 cycloserine Drugs 0.000 description 1
- 229960003843 cyproterone Drugs 0.000 description 1
- DUSHUSLJJMDGTE-ZJPMUUANSA-N cyproterone Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 DUSHUSLJJMDGTE-ZJPMUUANSA-N 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960002488 dalbavancin Drugs 0.000 description 1
- 108700009376 dalbavancin Proteins 0.000 description 1
- 229960000860 dapsone Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 229960002272 degarelix Drugs 0.000 description 1
- MEUCPCLKGZSHTA-XYAYPHGZSA-N degarelix Chemical compound C([C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CC=1C=CC(NC(=O)[C@H]2NC(=O)NC(=O)C2)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(NC(N)=O)C=C1 MEUCPCLKGZSHTA-XYAYPHGZSA-N 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229960002398 demeclocycline Drugs 0.000 description 1
- 239000000412 dendrimer Substances 0.000 description 1
- 229920000736 dendritic polymer Polymers 0.000 description 1
- 229960001251 denosumab Drugs 0.000 description 1
- 238000001739 density measurement Methods 0.000 description 1
- 230000000249 desinfective effect Effects 0.000 description 1
- 230000000368 destabilizing effect Effects 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 210000003275 diaphysis Anatomy 0.000 description 1
- YFAGHNZHGGCZAX-JKIFEVAISA-N dicloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(Cl)C=CC=C1Cl YFAGHNZHGGCZAX-JKIFEVAISA-N 0.000 description 1
- 229960001585 dicloxacillin Drugs 0.000 description 1
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 229960004100 dirithromycin Drugs 0.000 description 1
- WLOHNSSYAXHWNR-NXPDYKKBSA-N dirithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H]2O[C@H](COCCOC)N[C@H]([C@@H]2C)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 WLOHNSSYAXHWNR-NXPDYKKBSA-N 0.000 description 1
- NWOYIVRVSJDTLK-YSDBFZIDSA-L disodium;(2s,5r,6r)-6-[[(2r)-2-amino-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate;(1r,4s)-3,3-dimethyl-2,2,6-trioxo-2$l^{6}-thiabicyclo[3.2.0]heptane-4-carboxylate Chemical compound [Na+].[Na+].O=S1(=O)C(C)(C)[C@H](C([O-])=O)C2C(=O)C[C@H]21.C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C([O-])=O)(C)C)=CC=CC=C1 NWOYIVRVSJDTLK-YSDBFZIDSA-L 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 229960000895 doripenem Drugs 0.000 description 1
- AVAACINZEOAHHE-VFZPANTDSA-N doripenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](CNS(N)(=O)=O)C1 AVAACINZEOAHHE-VFZPANTDSA-N 0.000 description 1
- 229960003722 doxycycline Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960002549 enoxacin Drugs 0.000 description 1
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 description 1
- 229960002770 ertapenem Drugs 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 229960000285 ethambutol Drugs 0.000 description 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
- 229960002001 ethionamide Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 238000002710 external beam radiation therapy Methods 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 229960004273 floxacillin Drugs 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 229960002258 fulvestrant Drugs 0.000 description 1
- 229960001625 furazolidone Drugs 0.000 description 1
- PLHJDBGFXBMTGZ-WEVVVXLNSA-N furazolidone Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)OCC1 PLHJDBGFXBMTGZ-WEVVVXLNSA-N 0.000 description 1
- 229960004675 fusidic acid Drugs 0.000 description 1
- IECPWNUMDGFDKC-MZJAQBGESA-N fusidic acid Chemical compound O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C IECPWNUMDGFDKC-MZJAQBGESA-N 0.000 description 1
- 230000007045 gastrulation Effects 0.000 description 1
- 229960003923 gatifloxacin Drugs 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- QTQAWLPCGQOSGP-GBTDJJJQSA-N geldanamycin Chemical compound N1C(=O)\C(C)=C/C=C\[C@@H](OC)[C@H](OC(N)=O)\C(C)=C/[C@@H](C)[C@@H](O)[C@H](OC)C[C@@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-GBTDJJJQSA-N 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 229960003170 gemifloxacin Drugs 0.000 description 1
- ZRCVYEYHRGVLOC-HYARGMPZSA-N gemifloxacin Chemical compound C1C(CN)C(=N/OC)/CN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2C1CC1 ZRCVYEYHRGVLOC-HYARGMPZSA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 239000010440 gypsum Substances 0.000 description 1
- 229910052602 gypsum Inorganic materials 0.000 description 1
- MCAHMSDENAOJFZ-BVXDHVRPSA-N herbimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](OC)[C@@H](OC)C[C@H](C)[C@@H](OC)C2=CC(=O)C=C1C2=O MCAHMSDENAOJFZ-BVXDHVRPSA-N 0.000 description 1
- 229930193320 herbimycin Natural products 0.000 description 1
- 102000045875 human BMP1 Human genes 0.000 description 1
- 102000052974 human BMP10 Human genes 0.000 description 1
- 102000053736 human BMP15 Human genes 0.000 description 1
- 102000045896 human BMP2 Human genes 0.000 description 1
- 102000045888 human BMP3 Human genes 0.000 description 1
- 102000046148 human BMP4 Human genes 0.000 description 1
- 102000046096 human BMP5 Human genes 0.000 description 1
- 102000046095 human BMP6 Human genes 0.000 description 1
- 102000046107 human BMP7 Human genes 0.000 description 1
- 102000055779 human DEFB103A Human genes 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 230000000642 iatrogenic effect Effects 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000001524 infective effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000016507 interphase Effects 0.000 description 1
- NTHXOOBQLCIOLC-UHFFFAOYSA-N iohexol Chemical compound OCC(O)CN(C(=O)C)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NTHXOOBQLCIOLC-UHFFFAOYSA-N 0.000 description 1
- 229960001025 iohexol Drugs 0.000 description 1
- GKOZUEZYRPOHIO-IGMARMGPSA-N iridium-192 Chemical compound [192Ir] GKOZUEZYRPOHIO-IGMARMGPSA-N 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 229960003350 isoniazid Drugs 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 229960002437 lanreotide Drugs 0.000 description 1
- 108010021336 lanreotide Proteins 0.000 description 1
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 229960003376 levofloxacin Drugs 0.000 description 1
- 229960005287 lincomycin Drugs 0.000 description 1
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 description 1
- 229940041028 lincosamides Drugs 0.000 description 1
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 1
- 229960003907 linezolid Drugs 0.000 description 1
- 229960002422 lomefloxacin Drugs 0.000 description 1
- ZEKZLJVOYLTDKK-UHFFFAOYSA-N lomefloxacin Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNC(C)C1 ZEKZLJVOYLTDKK-UHFFFAOYSA-N 0.000 description 1
- 229960001977 loracarbef Drugs 0.000 description 1
- JAPHQRWPEGVNBT-UTUOFQBUSA-M loracarbef anion Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CC[C@@H]32)C([O-])=O)=O)N)=CC=CC=C1 JAPHQRWPEGVNBT-UTUOFQBUSA-M 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 229960003640 mafenide Drugs 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 229940021422 maxipime Drugs 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229960004616 medroxyprogesterone Drugs 0.000 description 1
- FRQMUZJSZHZSGN-HBNHAYAOSA-N medroxyprogesterone Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FRQMUZJSZHZSGN-HBNHAYAOSA-N 0.000 description 1
- 229960001786 megestrol Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229960002260 meropenem Drugs 0.000 description 1
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 1
- 229960004635 mesna Drugs 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000002923 metal particle Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- YPBATNHYBCGSSN-VWPFQQQWSA-N mezlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCN(S(C)(=O)=O)C1=O YPBATNHYBCGSSN-VWPFQQQWSA-N 0.000 description 1
- 229960000198 mezlocillin Drugs 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 231100000782 microtubule inhibitor Toxicity 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229940041009 monobactams Drugs 0.000 description 1
- 229960003702 moxifloxacin Drugs 0.000 description 1
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 description 1
- 229960003128 mupirocin Drugs 0.000 description 1
- 229930187697 mupirocin Natural products 0.000 description 1
- DDHVILIIHBIMQU-YJGQQKNPSA-L mupirocin calcium hydrate Chemical compound O.O.[Ca+2].C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC([O-])=O)OC1.C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC([O-])=O)OC1 DDHVILIIHBIMQU-YJGQQKNPSA-L 0.000 description 1
- 210000002346 musculoskeletal system Anatomy 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- JORAUNFTUVJTNG-BSTBCYLQSA-N n-[(2s)-4-amino-1-[[(2s,3r)-1-[[(2s)-4-amino-1-oxo-1-[[(3s,6s,9s,12s,15r,18s,21s)-6,9,18-tris(2-aminoethyl)-3-[(1r)-1-hydroxyethyl]-12,15-bis(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-h Chemical compound CC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O.CCC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O JORAUNFTUVJTNG-BSTBCYLQSA-N 0.000 description 1
- GPXLMGHLHQJAGZ-JTDSTZFVSA-N nafcillin Chemical compound C1=CC=CC2=C(C(=O)N[C@@H]3C(N4[C@H](C(C)(C)S[C@@H]43)C(O)=O)=O)C(OCC)=CC=C21 GPXLMGHLHQJAGZ-JTDSTZFVSA-N 0.000 description 1
- 229960000515 nafcillin Drugs 0.000 description 1
- 229960000210 nalidixic acid Drugs 0.000 description 1
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000002077 nanosphere Substances 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229960000808 netilmicin Drugs 0.000 description 1
- 229960000564 nitrofurantoin Drugs 0.000 description 1
- NXFQHRVNIOXGAQ-YCRREMRBSA-N nitrofurantoin Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)NC(=O)C1 NXFQHRVNIOXGAQ-YCRREMRBSA-N 0.000 description 1
- 230000001937 non-anti-biotic effect Effects 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 229960001180 norfloxacin Drugs 0.000 description 1
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 1
- 229960002700 octreotide Drugs 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- VHFGEBVPHAGQPI-MYYQHNLBSA-N oritavancin Chemical compound O([C@@H]1C2=CC=C(C(=C2)Cl)OC=2C=C3C=C(C=2O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O[C@@H]2O[C@@H](C)[C@H](O)[C@@](C)(NCC=4C=CC(=CC=4)C=4C=CC(Cl)=CC=4)C2)OC2=CC=C(C=C2Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]2C(=O)N[C@@H]1C(N[C@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@@H](O)[C@H](C)O1 VHFGEBVPHAGQPI-MYYQHNLBSA-N 0.000 description 1
- 229960001607 oritavancin Drugs 0.000 description 1
- 108010006945 oritavancin Proteins 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 210000004409 osteocyte Anatomy 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- UWYHMGVUTGAWSP-JKIFEVAISA-N oxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1 UWYHMGVUTGAWSP-JKIFEVAISA-N 0.000 description 1
- 229960001019 oxacillin Drugs 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960000625 oxytetracycline Drugs 0.000 description 1
- IWVCMVBTMGNXQD-PXOLEDIWSA-N oxytetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-PXOLEDIWSA-N 0.000 description 1
- 235000019366 oxytetracycline Nutrition 0.000 description 1
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 1
- 229960001723 oxytocin Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- KDLHZDBZIXYQEI-OIOBTWANSA-N palladium-103 Chemical compound [103Pd] KDLHZDBZIXYQEI-OIOBTWANSA-N 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
- UOZODPSAJZTQNH-LSWIJEOBSA-N paromomycin Chemical compound N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO UOZODPSAJZTQNH-LSWIJEOBSA-N 0.000 description 1
- 229960001914 paromomycin Drugs 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-L pemetrexed(2-) Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-L 0.000 description 1
- 229940056367 penicillin v Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 210000003460 periosteum Anatomy 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- BPLBGHOLXOTWMN-MBNYWOFBSA-N phenoxymethylpenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1 BPLBGHOLXOTWMN-MBNYWOFBSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229960002292 piperacillin Drugs 0.000 description 1
- 229940104641 piperacillin / tazobactam Drugs 0.000 description 1
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 description 1
- CSOMAHTTWTVBFL-OFBLZTNGSA-N platensimycin Chemical compound C([C@]1([C@@H]2[C@@H]3C[C@@H]4C[C@@]2(C=CC1=O)C[C@@]4(O3)C)C)CC(=O)NC1=C(O)C=CC(C(O)=O)=C1O CSOMAHTTWTVBFL-OFBLZTNGSA-N 0.000 description 1
- CSOMAHTTWTVBFL-UHFFFAOYSA-N platensimycin Natural products O1C2(C)CC3(C=CC4=O)CC2CC1C3C4(C)CCC(=O)NC1=C(O)C=CC(C(O)=O)=C1O CSOMAHTTWTVBFL-UHFFFAOYSA-N 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 239000004632 polycaprolactone Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920002338 polyhydroxyethylmethacrylate Polymers 0.000 description 1
- 229920000024 polymyxin B Polymers 0.000 description 1
- XDJYMJULXQKGMM-UHFFFAOYSA-N polymyxin E1 Natural products CCC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O XDJYMJULXQKGMM-UHFFFAOYSA-N 0.000 description 1
- KNIWPHSUTGNZST-UHFFFAOYSA-N polymyxin E2 Natural products CC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O KNIWPHSUTGNZST-UHFFFAOYSA-N 0.000 description 1
- 229960005266 polymyxin b Drugs 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229950004447 posizolid Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- ABBQGOCHXSPKHJ-WUKNDPDISA-N prontosil Chemical compound NC1=CC(N)=CC=C1\N=N\C1=CC=C(S(N)(=O)=O)C=C1 ABBQGOCHXSPKHJ-WUKNDPDISA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 229960005206 pyrazinamide Drugs 0.000 description 1
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 229940052337 quinupristin/dalfopristin Drugs 0.000 description 1
- BTTNOGHPGJANSW-IBGZPJMESA-N radezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(C=2C=CC(CNCC=3NN=NC=3)=CC=2)C(F)=C1 BTTNOGHPGJANSW-IBGZPJMESA-N 0.000 description 1
- 229950009965 radezolid Drugs 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 238000002278 reconstructive surgery Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000003014 reinforcing effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229960000885 rifabutin Drugs 0.000 description 1
- 229960002599 rifapentine Drugs 0.000 description 1
- WDZCUPBHRAEYDL-GZAUEHORSA-N rifapentine Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C(O)=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N(CC1)CCN1C1CCCC1 WDZCUPBHRAEYDL-GZAUEHORSA-N 0.000 description 1
- 229960003040 rifaximin Drugs 0.000 description 1
- NZCRJKRKKOLAOJ-XRCRFVBUSA-N rifaximin Chemical compound OC1=C(C(O)=C2C)C3=C4N=C5C=C(C)C=CN5C4=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O NZCRJKRKKOLAOJ-XRCRFVBUSA-N 0.000 description 1
- 229960005224 roxithromycin Drugs 0.000 description 1
- KJTLSVCANCCWHF-BKFZFHPZSA-N ruthenium-106 Chemical compound [106Ru] KJTLSVCANCCWHF-BKFZFHPZSA-N 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229960003600 silver sulfadiazine Drugs 0.000 description 1
- UEJSSZHHYBHCEL-UHFFFAOYSA-N silver(1+) sulfadiazinate Chemical compound [Ag+].C1=CC(N)=CC=C1S(=O)(=O)[N-]C1=NC=CC=N1 UEJSSZHHYBHCEL-UHFFFAOYSA-N 0.000 description 1
- 235000021309 simple sugar Nutrition 0.000 description 1
- 231100001055 skeletal defect Toxicity 0.000 description 1
- 229960000268 spectinomycin Drugs 0.000 description 1
- UNFWWIHTNXNPBV-WXKVUWSESA-N spectinomycin Chemical compound O([C@@H]1[C@@H](NC)[C@@H](O)[C@H]([C@@H]([C@H]1O1)O)NC)[C@]2(O)[C@H]1O[C@H](C)CC2=O UNFWWIHTNXNPBV-WXKVUWSESA-N 0.000 description 1
- 229960001294 spiramycin Drugs 0.000 description 1
- 235000019372 spiramycin Nutrition 0.000 description 1
- 229930191512 spiramycin Natural products 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 229960002673 sulfacetamide Drugs 0.000 description 1
- SKIVFJLNDNKQPD-UHFFFAOYSA-N sulfacetamide Chemical compound CC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 SKIVFJLNDNKQPD-UHFFFAOYSA-N 0.000 description 1
- 229960000973 sulfadimethoxine Drugs 0.000 description 1
- ZZORFUFYDOWNEF-UHFFFAOYSA-N sulfadimethoxine Chemical compound COC1=NC(OC)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 ZZORFUFYDOWNEF-UHFFFAOYSA-N 0.000 description 1
- 229960000654 sulfafurazole Drugs 0.000 description 1
- 229960005158 sulfamethizole Drugs 0.000 description 1
- VACCAVUAMIDAGB-UHFFFAOYSA-N sulfamethizole Chemical compound S1C(C)=NN=C1NS(=O)(=O)C1=CC=C(N)C=C1 VACCAVUAMIDAGB-UHFFFAOYSA-N 0.000 description 1
- 229960005404 sulfamethoxazole Drugs 0.000 description 1
- 229950008188 sulfamidochrysoidine Drugs 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 1
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 description 1
- 238000004381 surface treatment Methods 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- XFALPSLJIHVRKE-GFCCVEGCSA-N tedizolid Chemical compound CN1N=NC(C=2N=CC(=CC=2)C=2C(=CC(=CC=2)N2C(O[C@@H](CO)C2)=O)F)=N1 XFALPSLJIHVRKE-GFCCVEGCSA-N 0.000 description 1
- 229960001608 teicoplanin Drugs 0.000 description 1
- ONUMZHGUFYIKPM-MXNFEBESSA-N telavancin Chemical compound O1[C@@H](C)[C@@H](O)[C@](NCCNCCCCCCCCCC)(C)C[C@@H]1O[C@H]1[C@H](OC=2C3=CC=4[C@H](C(N[C@H]5C(=O)N[C@H](C(N[C@@H](C6=CC(O)=C(CNCP(O)(O)=O)C(O)=C6C=6C(O)=CC=C5C=6)C(O)=O)=O)[C@H](O)C5=CC=C(C(=C5)Cl)O3)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](NC(=O)[C@@H](CC(C)C)NC)[C@H](O)C3=CC=C(C(=C3)Cl)OC=2C=4)O[C@H](CO)[C@@H](O)[C@@H]1O ONUMZHGUFYIKPM-MXNFEBESSA-N 0.000 description 1
- 229960005240 telavancin Drugs 0.000 description 1
- 108010089019 telavancin Proteins 0.000 description 1
- 229960003250 telithromycin Drugs 0.000 description 1
- LJVAJPDWBABPEJ-PNUFFHFMSA-N telithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)[C@@H](C)C(=O)O[C@@H]([C@]2(OC(=O)N(CCCCN3C=C(N=C3)C=3C=NC=CC=3)[C@@H]2[C@@H](C)C(=O)[C@H](C)C[C@@]1(C)OC)C)CC)[C@@H]1O[C@H](C)C[C@H](N(C)C)[C@H]1O LJVAJPDWBABPEJ-PNUFFHFMSA-N 0.000 description 1
- BVCKFLJARNKCSS-DWPRYXJFSA-N temocillin Chemical compound N([C@]1(OC)C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C(C(O)=O)C=1C=CSC=1 BVCKFLJARNKCSS-DWPRYXJFSA-N 0.000 description 1
- 229960001114 temocillin Drugs 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- 150000003515 testosterones Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- OTVAEFIXJLOWRX-NXEZZACHSA-N thiamphenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CO)NC(=O)C(Cl)Cl)C=C1 OTVAEFIXJLOWRX-NXEZZACHSA-N 0.000 description 1
- 229960003053 thiamphenicol Drugs 0.000 description 1
- 229960004089 tigecycline Drugs 0.000 description 1
- 229960005053 tinidazole Drugs 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- 229960005041 troleandomycin Drugs 0.000 description 1
- LQCLVBQBTUVCEQ-QTFUVMRISA-N troleandomycin Chemical compound O1[C@@H](C)[C@H](OC(C)=O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](C)C(=O)O[C@H](C)[C@H](C)[C@H](OC(C)=O)[C@@H](C)C(=O)[C@@]2(OC2)C[C@H](C)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)OC(C)=O)[C@H]1C LQCLVBQBTUVCEQ-QTFUVMRISA-N 0.000 description 1
- 230000001549 tubercolostatic effect Effects 0.000 description 1
- 230000000766 tuberculocidal effect Effects 0.000 description 1
- 239000000814 tuberculostatic agent Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
- 210000003171 tumor-infiltrating lymphocyte Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- KGPGQDLTDHGEGT-JCIKCJKQSA-N zeven Chemical compound C=1C([C@@H]2C(=O)N[C@H](C(N[C@H](C3=CC(O)=C4)C(=O)NCCCN(C)C)=O)[C@H](O)C5=CC=C(C(=C5)Cl)OC=5C=C6C=C(C=5O[C@H]5[C@@H]([C@@H](O)[C@H](O)[C@H](O5)C(O)=O)NC(=O)CCCCCCCCC(C)C)OC5=CC=C(C=C5)C[C@@H]5C(=O)N[C@H](C(N[C@H]6C(=O)N2)=O)C=2C(Cl)=C(O)C=C(C=2)OC=2C(O)=CC=C(C=2)[C@H](C(N5)=O)NC)=CC=C(O)C=1C3=C4O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O KGPGQDLTDHGEGT-JCIKCJKQSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
- A61L27/3645—Connective tissue
- A61L27/365—Bones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/025—Other specific inorganic materials not covered by A61L27/04 - A61L27/12
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/12—Phosphorus-containing materials, e.g. apatite
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
- A61L27/3608—Bone, e.g. demineralised bone matrix [DBM], bone powder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
- A61L2300/406—Antibiotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
Definitions
- the present invention relates to the field of treatment of bone defects.
- the invention provides a composition for treatment of bone defects.
- Bone defects represent a common orthopaedic problem and can be a significant challenge to treat. They can arise as a consequence of disturbances or failure of formation and/or differentiation (bone aplasias and dysplasias), trauma, destruction due to a pathological process (infection, inflammation, tumors and implant wear associated osteolysis) or a surgical intervention or any combination of these.
- MBD metastatic bone disease
- US2004/157798 A1 discloses the use of bisphosphonates (e.g. zoledronate) for improving the osteoinductive and/or osteoconductive potential of bone graft substitutes or extenders (e.g. ProOsteon: hydroxyapatite and calcium carbonate) when said bone graft substitutes or extenders are used in combination with a bone graft (autogenous bone graft, allograft, xenograft) or with each other.
- the extender may be mixed with antibiotics or can comprise BMP-7, -2, -4, -6.
- Disclosed are methods of performing bone grafting in a patient said methods including the steps of: delivering a bone graft, bone graft substitute, an extender or a combination thereof to a graft site; and administering a drug selected from at least one bisphosphonate to the patient to increase the osteoinductive and/or osteoconductive potential of the bone graft, bone graft substitute or the extender.
- This method relates to the alternative and subsequent use of a bioactive agent possibly in a biocompatible carrier and a biocompatible matrix.
- Bisphosphonates are used for improving the osteoinductive and/or osteoconductive potential of bone graft substitutes or extenders when said bone graft substitutes or extenders are used in combination with a bone graft or with each other.
- Drawbacks of conventional bone graft substitutes include delayed or absent resorption, which may restrict or even block bone ingrowth and formation of new bone.
- some bone graft substitutes are associated with unpredictable in situ maintenance of their solid structure, which has led to treatment cases where adequate mechanical stability of the bone reconstruction construct was not sufficiently maintained and a stable osteoconductive scaffold was not achieved.
- the present invention provides a multi-phasic biodynamic scaffold useful for assembly and for building in situ to accommodate the individual characteristic of the individual bone defect.
- the invention thus provides a bone reconstruction composition according to claim 1.
- the present invention also provides a composition according to claim 3.
- the present invention also provides a composition for use in the treatment of a bone defect, according to claim 6.
- kit-of-parts may be used in a layered application and subsequent impaction achieves a firmly interdigitated three dimensionally solid composite structure. After curing of the composite filling the interspaces, said structure optimally fits the individual defect geometry and has vastly improved mechanical properties making it substantially more resistant to bending and shears forces. Thus, typically after 6 weeks and even more after 3 to 6 month from surgery, bone re-growth and remodeling is observed and there is no sign of liquefaction of the composite, as can also be seen from the pictures in the drawings.
- the disclosure also provides a method for treatment of a bone defect in an individual in need thereof, which method comprises
- the present disclosure also provides a method for bone reconstruction in an individual suffering from a bone defect, said method comprising performing the method according to any one of the preceding claims, thereby obtaining growth of healthy bone on the site of the bone defect in said individual.
- the invention also provides kit-of-parts according to claim 5.
- biocompatible matrix refers to a composition comprising solid particles and/or scaffolds of natural or synthetic origin.
- Said biocompatible matrix is preferably mechanically stable, and thus may be capable of providing mechanical stability to bone.
- Said particles and/or scaffolds are biocompatible meaning that they can coexist with living tissues without causing harm.
- Preferably said particles may slowly be resorbed by osteoclasts and subsequently replaced by newly formed bone through osteoblastic activity, or alternatively, the particles may permanently osseointegrate.
- osteointegrate it is understood that a direct structural and functional connection is formed between living bone and the surface of the particles and/or scaffolds, for example hydroxyapatite, allograft bone or metal particles and/or scaffolds.
- the biocompatible matrix may be resorbable, slowly resorbable or non-resorbable.
- the biocompatible matrix may comprise or consist of a bone graft material.
- the particles may comprise or consist of one or more selected from the group consisting of bone graft material (e.g. autograft and/or allograft bone graft material), synthetic metallic particles and/or scaffolds, synthetic non-metallic particles and/or scaffolds and any combination thereof.
- biocompatible carrier refers to a composition comprising materials of natural or synthetic origin (e.g. calcium salts, polymers, collagen gels) which can coexist with living tissues without causing harm and are suitable vehicles for delivery of any bioactive agent to a living tissue, for example to the site of a bone defect.
- the biocompatible carrier is an osteoconductive carrier.
- the biocompatible carrier comprises an osteoconductive material.
- osteoconductive refers to a material that can serve as a scaffold for new bone growth that is perpetuated by the native bone. Osteoblasts from the margin of the defect that is being treated can utilize the osteoconductive material as a framework upon which to spread and generate new bone.
- An "osteoconductive material” is usually a material that can be in powder form, but can become a paste when mixed with a solvent. The so-formed paste can subsequently cure at physiological conditions e.g. in the site of a bone defect.
- bone refers to natural bone from any animal. Bones typically comprise cortical bone and cancellous bone. Bone may also comprise other types of tissue, which may be referred to collectively as "soft tissue".
- soft tissues include marrow, endosteum, periosteum, nerves, blood vessels and cartilage.
- bone graft material refers to a material comprising bone from a human or non-human animal.
- bone graft material consists exclusively of material from bone from a human or non-human animal.
- Bone graft material is preferably divided in particles.
- cancellous bone also known as trabecular bone or spongy bone, as used herein refers to the bone composed of tiny lattice-shaped units, typically located internal to the hard compact bone at the metaphyeal ends of the long bones.
- cur refers to hardening of the composition. After mixing all ingredients of the bone reconstruction composition, the composition starts curing. The composition is considered “cured” if digital compression does not leave an impression.
- paste refers to a composition of a sufficient high viscosity to allow physical application to a defined space without losing its shape. A composition is considered a "paste", when the interphase between the paste and surrounding air is not deformed when a container comprising the paste is being moved.
- individual refers to a human or non-human animal.
- resorbable refers to a material that can be targeted by osteoclasts, dissolved, and subsequently replaced by newly formed bone through osteoblastic activity.
- Resorbable materials can be polymers, ceramics, or composites. Examples of resorbable materials are calcium sulfate, calcium phosphate, hydroxyapatite, polymers, e.g. polylactcic acid, collagen foams or gels.
- treatment may refer to any kind of treatment.
- the treatment may be a curative treatment, or it may also be an ameliorating treatment and/or a treatment reducing the effects of the bone defect.
- the treatment may also be a treatment which delays progression of a bone defect, for example the treatment may reduce the growth of metastatic bone disease.
- kits-of-parts for bone reconstruction typically comprise a bone reconstruction composition and a biocompatible matrix.
- the biocompatible matrix may comprise or consist of a bone graft material. Examples of useful biocompatible matrices are described below.
- the bone reconstruction composition may comprise a biocompatible carrier and at least one bioactive agent.
- the bone reconstruction composition may comprise an osteoconductive material. Examples of useful biocompatible carriers and bioactive agents are provided below.
- the osteoconductive material comprises or consists of hydroxyapatite and calcium salts.
- the at least one bioactive agent may be an antiresoprtive agent, such as a bisphosphonate.
- Said bone reconstruction composition may also comprise two or more bioactive agents that can add further beneficial effects for bone reconstruction.
- bioactive agents are anti-microbial agents, antiresorptive agents, anti-tumor agents, bone growth-promoting osteoinductive and/or osteogenetic agents, and more as described in the section below "Bioactive agents”.
- Said bone reconstruction composition may also comprise a solvent.
- the bone reconstruction composition comprises a bioactive agent which is in liquid form and can act as a solvent.
- the invention also provides a bone reconstruction composition per se, which comprises calcium sulfate and/or calcium phosphate, an antiresorptive agent comprising or consisting of bisphosphonate, and fosfomycin.
- a bone reconstruction composition per se which comprises calcium sulfate and/or calcium phosphate, an antiresorptive agent comprising or consisting of bisphosphonate, and fosfomycin.
- an antiresorptive agent comprising or consisting of bisphosphonate
- fosfomycin fosfomycin.
- useful biocompatible carriers, bisphosphonates, anti-microbial agents and other bioactive agents are provided below.
- the bone reconstruction composition and the kit-of-parts are preferably prepared in such a way that they can be used to repair bone defects in vivo and stimulate bone growth in a subject affected by a bone defect.
- the bone reconstruction composition achieves a viscosity, which is sufficiently high so that it does not flow away from the site of the bone defect when added to said site.
- the bone reconstruction material should preferably be moldable for a sufficient amount of time to allow for optimal adaptation to the individual site and geometry during repair of the bone defect.
- the bone reconstruction composition may reach a beneficial degree of hardness within 2 to 60 minutes from mixing.
- the bone reconstruction composition cures in a time range of 2 to 120 min, such as in the range of 2 to 60 minutes, for example in the range of 30 to 60 min. after all ingredients of said composition are mixed.
- the bone reconstruction composition hardens to a paste in a time range of 2 to 10 minutes, such as in a time range of 2 to 5 minutes, such as in a time range of 2 to 3 minutes after all ingredients of said composition are mixed.
- the bone reconstruction composition thickens to a paste in a time range of 2 to 10 minutes, such as in a time range of 2 to 5 minutes, such as in a time range of 2 to 3 minutes after all ingredients of said composition are mixed.
- the bone reconstruction compositions may also comprise bioactive agents and therapeutic agents such as anti-microbial agents and/or antiresorptive agents, anti-tumor agents and growth-promoting agents that facilitate, enhance or protect the bone reconstruction.
- bioactive agents and therapeutic agents such as anti-microbial agents and/or antiresorptive agents, anti-tumor agents and growth-promoting agents that facilitate, enhance or protect the bone reconstruction.
- bioactive agents and therapeutic agents may be released from the composition to the tissues around it in vivo in the treated individual. Examples of said bioactive agents are provided below.
- At least one bioactive agent is an antibiotic, as described in the section "Antibiotic”.
- at least one bioactive agent is an antiresorptive agent.
- the antiresorptive agent may be one of the bisphosphonates described in the section "Bisphosphonate”.
- the bone reconstruction composition may comprise a growth promoting agent, which may be any of the bioactive agents described in the section "Growth promoting agent”.
- the bone reconstruction composition may comprise any of the bioactive agents described herein below in the sections "Bioactive agent”, “Bisphosphonate”, “Antimicrobial agents", “Growth promoting agents” and “Other bioactive agents”.
- the bone reconstruction composition may comprise both an antibiotic and an antiresorptive agent.
- the bone reconstruction may comprise only one of an antibiotic or an antiresorptive agent.
- the bone reconstruction composition may also comprise one or more additional bioactive agents.
- the main components comprised in the bone reconstruction composition may have any of the features described in the following sections "Biocompatible carrier”, “Bioactive agent”, “Hydroxyapatite”, “Bisphosphonate”, “Calcium salt”, “Antibiotic”, and “Growth factor”.
- the kit-of-parts according to the invention typically comprises the bone reconstruction composition and a biocompatible matrix.
- the biocompatible matrix comprises solid particles of natural origin. Said particles may be bone graft material, such as bone from a human or a non-human animal, and may be any of the materials described herein below in the section "Biocompatible matrix".
- the parts of the kit may be provided and stored separately.
- Said kit-of-parts may be prepared for contacting the site of a bone defect in an individual in need thereof with alternating layers of bone reconstruction composition and biocompatible matrix such as a bone graft material in order to achieve the important mechanical stability of the resulting bone reconstruction construct to provide a mechanically undisturbed environment conductive to bone graft incorporation, remodeling and overall healing.
- biocompatible matrix such as a bone graft material
- Examples of useful methods for contacting the site of a bone defect are described herein below in the section "Treatment of bone defect”.
- Said biocompatible matrix may be any of the materials described in the section below "Biocompatible matrix”.
- the bone reconstruction composition may be replaced by the healthy growing bone of the subject, said bone growing because of the beneficial effects of the compositions and methods described in the present invention.
- compositions for bone reconstruction comprising providing a composition that promotes bone reconstruction, providing a biocompatible matrix e.g. a bone graft material, and providing impacting a bone defect with said composition and said biocompatible matrix in alternate layers.
- the composition may comprise different components as described in the section "Compositions for bone reconstruction”.
- a bone defect is treated using the method as disclosed herein and described in detail in the section below "Method for bone reconstruction”.
- the treatment comprises local administration of a composition and a bone graft material to a subject affected by a bone defect thereby allowing growth of healthy bone in place of a bone defect.
- the method involves contacting the site of bone defect with alternating layers of said bone reconstruction composition and said biocompatible matrix e.g. a bone graft material.
- said biocompatible matrix e.g. a bone graft material.
- This in-situ additive layering may start with contacting the entire bone walls of the site of bone defect with the bone reconstruction composition. This may ensure that the biologically most active substances are delivered as close as possible to the target zone of initial remodeling and potential residual pathology.
- Said bone reconstruction composition is typically delivered in the form of a paste. After addition of said bone reconstruction composition the biocompatible matrix may be added.
- the bone reconstruction composition and the biocompatible matrix e.g. a bone graft material are applied to the bone defect by injection and/or moulding.
- the method may comprise the steps of:
- the method may comprise contacting the site of the bone defect with one or more active compounds, e.g. with an antiresorptive agent, such as a bisphosphonate, with an antimicrobial agent such as an antibiotic and/or with a growth promoting agent, such as a BMP.
- an antiresorptive agent such as a bisphosphonate
- an antimicrobial agent such as an antibiotic
- a growth promoting agent such as a BMP.
- Zoledronic acid or a pharmaceutically acceptable salt thereof is administered locally to the site of the bone defect prior to performing step a).
- bone density measurements with dual energy x/ray absorptiometry are performed before and after treatment to assess the state of the bone.
- the values do not change significantly in the time following treatment with the kit-of-parts and methods according to the present invention.
- Exemplary values before treatment are at least 1.5 g/cm 2 and not higher than 3 g/cm 2 . In an individual treated with traditional methods, said values would typically drop to at least 0.1 g/cm 2 and not higher than 1 g/cm 2 after treatment.
- said values would remain constant and thus be at least 1.5 g/cm 2 and not higher than 3 g/cm 2 after at least 6 weeks, such as at least 12 weeks after treatment, indicating that bone has replaced the composition.
- the methods for treatment of a bone defect in a subject disclosed herein may be supplemented by the use of appropriate internal or external bone fixation devices to establish or protect mechanical integrity of the entire bone in which the defect is treated.
- therapeutic- and/or preventive antimicrobial biofilm agent application to the surface of the implant may be needed.
- the bioactive agents described in the sections "Bioactive agents”, “Antibiotics” and “Other bioactive agents” can be used for this purpose.
- Said agents may be applied as preliminary surface treatment (e.g. surface coating with antimicrobial agents such as silver, copper, antibiotics or others).
- Said agents may also be used for in-situ surface modification of the surface of the implant e.g. with antibiotic- and/or antibiofilm agents.
- the biocompatible carrier comprises at least one bioactive agent, wherein said bioactive agent prevents and/or treats microbial colonization and biofilm formation of the particles of the biocompatible matrix.
- the biocompatible carrier comprises at least one bioactive agent, wherein said bioactive agent prevents and/or treats microbial colonization and biofilm formation of any internal or external bone fixation device used for treating a bone defect.
- kits-of-parts and bone reconstruction compositions that are useful for treatment of a variety of bone defects in a subject.
- said individual may be an individual suffering from cancerous bone diseases, for example metastatic bone lesions; primary bone cancer, for example osteosarcoma; benign bone tumors, for example giant cell tumor of bone; inflammation or infection of the bones; and one or more bone fractures, for example pathologic fractures, and thus, said bone defect may be any of the aforementioned or caused by any of the aforementioned conditions.
- the bone reconstruction compositions, the kits-of-parts as well as the methods can also be used to reconstruct a gap, a bone void, or a pre-existing bone cavity.
- the bone defect may be a partial or complete structural gap, a so-called segmental bone defect, or a bone void or a pre-existing bone cavity, so-called cavitary bone defect.
- the bone reconstruction compositions, the kits-of-parts as well as the methods can be used in a wide variety of applications, such as in the treatment of bone defects associated with trauma and fracture healing, prosthetic implants, and implants of foreign materials in other situations and bone loss due to congenital, infective or iatrogenic causes.
- Such situations may comprise filling a gap or a bone void or a pre-existing bone cavity, such as fractures, osteotomy, for the attachment of prostheses or other foreign material, for prosthetic revision surgery, for plastic surgery, for reconstruction surgery, or for cosmetic surgery.
- the bone reconstruction compositions, the kits-of-parts as well as the methods are suitable for local use in tooth pockets and/or bifurcatures to treat periodontitis or to be combined with other treatment options for periodontitis included therein, such as supportive matrix proteins or locally acting growth inducing factors.
- the bone reconstruction compositions, the kits-of-parts as well as the methods can be used for repairing osteochondral defects as well as fractures or bone defects involving a joint.
- the bone reconstruction compositions, the kits-of-parts as well as the methods can be used to fill skeletal defects caused by the removal of orthopedic devices, which are utilized for internal or external fixation of fractures, for example screws and pin tracts. It is in such occasions preferred that antibiotics are included in the composition as additives. They can also be used for filling of a bone cavity or replacing bone lost during surgical removal of a tumor.
- the bone reconstruction compositions, the kits-of-parts as well as the methods can be used for local treatment of infections or infestations in the musculoskeletal system, such as osteomyelitis caused by e.g. bacteria or fungi.
- a combined osteoplastic and local antimicrobial treatment and a prophylaxis of skeletal infection can thus be obtained, e.g. in sternotomies, prosthetic implants, reconstructive surgery, trauma surgery, cancer surgery, cosmetic surgery, and oro-maxillo-facial surgery.
- the bone reconstruction compositions, the kits-of-parts as well as the methods can also be used for local treatment with cytostatic or anti-tumor agents, such as in musculoskeletal tumors, e. g. for treatment of metastases in bone, e.g. in vertebrae.
- the metastases may be from any primary cancer, such as breast or prostatic cancers.
- the primary cancer may be a cancer demanding treatment with a supportive material that concomitantly gives a possibility for local treatment with anti-tumor agents.
- it can be used locally together with agents that enhance the clinical effects of irradiation in diseases, such as tumor diseases.
- a list of relevant anti-tumor agents that can be incorporated in the bone reconstruction composition as bioactive agents can be found on https://www.cancer.gov/about-cancer/treatment/drugs .
- the bone defect is caused by an inflammation and/or by an infection of the bone.
- the bone defect is a bone tumor, such as giant cell tumor of bone and/or the bone defect is associated with or caused by a bone tumor, such as giant cell tumor of bone.
- the bone defect is metastatic bone disease.
- Many primary tumors metastasize to other locations in the body, for example bone.
- Cancer which has metastasized to bone may be referred to as "metastatic bone disease”.
- a metastasis to the bone may cause bone cavities.
- metastases may be removed from the bone by surgery leaving a bone cavity.
- Bone cavities caused by or associated with metastases to the bone may be filled using the bone reconstruction compositions, the kits-of-parts and/or the methods of the present invention.
- the bone reconstruction compositions described by the present disclosure comprise a biocompatible carrier.
- Said biocompatible carrier may be a controlled releasing polymer matrix, for example comprising a synthetic polymer, such a synthetic polymer with pendant-functionalized diols, polyethylene glycol, polyacrylic acid, polyesters and their co-plymers e.g. polycaprolactone, polyanhydrides e.g. polyanhydrides based on sebacic acid (SA), p-(carboxyphenoxy)propane (CPP), p-(carboxyphenoxy)hexane (CHP) and their copolymers, polyamides, polyorthoesters (POE), e.g. POE I, POE II, POE III and POE IV; recombinant proteins-based polymers, in-situ forming hydrogels (such as PHEMA, and copolymers of PVA or PEG with acrylamides).
- a synthetic polymer such as synthetic polymer with pendant-functionalized diols, polyethylene glycol, polyacrylic acid, polyesters and their co
- Said biocompatible carrier may be a controlled releasing polymer matrix, for example comprising a natural polymer e.g. proteins such as collagen, gelatin and fibrin; polysaccharides such as hyaluronic acid and alginate; cellulose derivatives, chitosan, polysaccharide-based polymers and natural protein-based polymers.
- a natural polymer e.g. proteins such as collagen, gelatin and fibrin
- polysaccharides such as hyaluronic acid and alginate
- cellulose derivatives, chitosan polysaccharide-based polymers and natural protein-based polymers.
- Said biocompatible carrier comprising a releasing polymer matrix may comprise polymers as described above in pure form or as part of drug delivery systems such as nanoparticles and microparticles, dendrimers, nano- and micro-spheres, capsosomes and micelles.
- the biocompatible carrier comprised in the bone reconstruction composition comprises an osteoconductive resorbable material.
- the biocompatible carrier is typically used as a carrier for one or more bioactive agents.
- the bioactive agents may further enhance the growth of the natural bone and/or have a therapeutic effect for treatment of the bone defect or a disease associated therewith.
- the biocompatible carrier comprises an osteoconductive material and so it favors growth of natural bone via the action of osteoblasts and osteoclasts. In other embodiments, the biocompatible carrier does not comprise an osteoconductive material.
- the biocompatible carrier comprises calcium salts and/or hydroxyapatite, as described below.
- the biocompatible carrier comprises hydroxyapatite and polymers. It is preferred that the biocompatible carrier comprises both calcium salt(s) and hydroxyapatite, which may be any of the calcium salts and hydroxyapatites described below.
- the biocompatible carrier of the present disclosure may comprise calcium salts.
- Said calcium salt may be any useful calcium salt.
- the calcium salt may be selected from the group consisting of calcium sulfate and calcium phosphate.
- the biocompatible carrier comprises more than one calcium salt, and thus the calcium salt may be a mixture of at least two different calcium salts.
- the calcium salt may for example comprise at least one calcium phosphate component and at least one calcium sulfate component.
- the calcium salt comprises only one calcium salt.
- Calcium sulfate may particularly be hardened calcium sulfate, such as hardened calcium sulfate that has a diameter which is less than 100 ⁇ m.
- calcium sulfate represent up to 100% of the calcium salts.
- the particulate hardened calcium sulfate is calcium sulfate dihydrate (gypsum).
- the biocompatible carrier does not comprise calcium sulfate.
- the biocompatible carrier of the present disclosure may comprise the calcium-rich mineral hydroxyapatite (HA).
- HA is a naturally occurring mineral and has the general formula Ca 5 (PO 4 ) 3 (OH), usually written Ca 10 (PO 4 ) 6 (OH) 2 because its crystal unit is a dimer.
- Ca 5 (PO 4 ) 3 (OH) usually written Ca 10 (PO 4 ) 6 (OH) 2 because its crystal unit is a dimer.
- Up to 50% by volume and 7% by weight of human bone is a modified form of HA and HA is also known as bone mineral.
- the HA is mixed with the calcium salt.
- the ratio between the calcium salt and HA is typically in the following ranges:
- the bone reconstruction composition may comprise at least 40% of said mixture of HA and calcium salt, for example at least 50% of said mixture of HA and calcium salt, such as in the range of 40 to 70%, for example in the range of 50 to 70%, such as in the range of 50 to 60% of said mixture of HA and calcium salt.
- the bone reconstruction compositions described by the present disclosure comprise at least one bioactive agent.
- the at least one bioactive agent is usually comprised in the biocompatible carrier.
- a bioactive agent is applied directly to the solid components of the biocompatible matrix, for example silver or hydroxyapatite can be used to coat trabecular titanium spheres, or antibiotics, anti-biofilm and antiresorptive agents can be adsorbed onto purified allograft bone.
- the bone reconstruction composition of the present disclosure comprises, in some embodiments, two or more bioactive agents, wherein any one of the two or more bioactive agent is any one of the bioactive agents described herein.
- the bone reconstruction composition is in the form of a paste and comprises two or more bioactive agents, wherein at least one of the bioactive agents accelerates curing of the paste and wherein at least one of the bioactive agents decelerates curing of the paste.
- an agent that accelerates curing of the composition may be added.
- Said agent that accelerates curing of the bone reconstruction composition and improves its stability may be added by titration.
- the bioactive agent that accelerates curing of the composition is fosfomycin or a pharmaceutically acceptable salt thereof.
- the bioactive agent that accelerates curing of the composition is fosfomycin or a pharmaceutically acceptable salt thereof and said fosfomycin or a pharmaceutically acceptable salt thereof is dissolved in a solvent.
- the bioactive agent that decelerates curing of the composition is a bisphosphonate, for example a bisphosphopnate selected from a group consisting of Zoledronic acid, Pamidronic acid, Neridronic acid, Olpadronic acid, Alendronic acid, Ibandronic acid, Risedronic acid, pharmaceutically acceptable salts of any of the aforementioned and combinations of any of the aforementioned .
- the bone reconstruction composition may comprise a bisphosphonate in an amount comprised between 0.08 and 0.2g/ml, so 10 ml of compositions may comprise between 0.8 and 2 g of bisphosphonate.
- the bone reconstruction compositions comprise a bisphosphonate.
- bisphosphonate refers to a class of medicaments that prevent the loss of bone mass. This class of medicaments is also referred to as antiresorptive agents, as they slow or block the resorption of bone.
- the antiresorptive agent used is a bisphosphonate.
- the antiresorptive agent is a compound having antiresorptive activity but not the structure of a bisphosphonate, for example a monoclonal antibody such as Denosumab.
- bisphosphonates to be used with the present invention have the general structure of formula (I):
- the bisphosphonates to be used with the present invention are preferably compounds of formula (I), which are specific inhibitors of osteoclasts. By inhibiting osteoclasts, the bisphosphonates inhibit bone loss.
- R' may be a small moiety, for example R' may be selected from the group consisting of -H, -OH and halogen.
- R' is -OH, which enhances binding to hydroxyapatite.
- R" may be a larger moiety although it is also comprised in the invention that R" may be a small moiety such as halogen or methyl.
- R" is -C 1-6 -alkyl-X, wherein X is selected from the group consisting of cyclic, aryl, heteroaryl and amine.
- X may be amine or a mono- or bicyclic heteroaryl, wherein at least one heteroatom of said heteroaryl is nitrogen.
- Said amine may be a primary amine, for example -NH 2 , a secondary amine or a tertiary amine.
- Said tertiary amine may be - N(R 1 )(R 2 ), wherein R 1 and R 2 independently are C 1-6 -alkyl.
- Said mono- or bicyclic heteroaryl, wherein at least one heteroatom of said heteroaryl is nitrogen may for example be imidazole, pyridine or pyrrolidine.
- the bisphosphonate is a nitrogen containing bisphosphonate.
- the bisphosphonate may be a bisphosphonate of formula (I), wherein at least one of R' and R" contains nitrogen.
- the bisphosphonate is selected from the group consisting of Zoledronic acid, Pamidronic acid, Neridronic acid, Olpadronic acid, Alendronic acid, Ibandronic acid, Risedronic acid and pharmaceutically acceptable salts thereof.
- the bone reconstruction compositions may also comprise more than one bisphosphonate, for example the bone reconstruction compositions may comprise a combination of two or more of the aforementioned bisphosphonates.
- the bisphosphonate is a nitrogen containing bisphosphonate, for example selected from the group consisting of Zoledronic acid, Alendronic acid, Risedronic acid and pharmaceutically acceptable salts thereof.
- the bisphosphonate is Zoledronic acid (ZA) or a pharmaceutically acceptable salt thereof.
- the bisphosphonate may be Zoledronic acid.
- Zoledronic acid may also be referred to as zoledronate.
- Zoledronic acid is a compound of the formula (II):
- Zoledronate has multiple anti-tumor effects, including direct induction of cell death in various types of tumor, such as lung-, breast, prostate and kidney cancer, myeloma and giant cell tumor of bone.
- the bisphosphonate may be present within the composition in any suitable amount.
- the bone reconstruction composition may comprise in the range of 0.1 to 1.5 mg/ml, such as in the range of 0.2 to 1 mg/ml, for example in the range of 0.2 to 0.0 mg/ml, such as in the range of 0.3 to 0.8 mg/ml of said bisphosphonate.
- the bone reconstruction composition comprises approximately 0.3 mg/ml of bisphosphonate.
- the bone reconstruction composition comprises approximately 0.55 mg/ml.
- the bone reconstruction composition comprises approximately 0.80 mg/ml.
- ml refers to the final volume of the bone reconstruction composition and the term "approximately" as used herein refers to +/-10%, such as +/- 5%, for example +/-1%.
- 10 ml of bone reconstructing composition comprises between 1 and 2.5 ml of said Zoledronic acid or pharmaceutically acceptable salt thereof, such as between 1 and 1.5 ml, such as between 1 and 2 ml, such as between 1. 5 and 2 ml, such as between 1.5 and 2.5 ml, such as between 2 and 2.5 ml f said Zoledronic acid or pharmaceutically acceptable salt thereof.
- 10 ml of bone reconstructing composition comprises between 0.2 and 2 g of said Zoledronic acid or pharmaceutically acceptable salt thereof, such as between 0.2 and 1.5 g, such as between 0.2 and 1 g, such as between 0.2 and 0.5 g, such as between 0.5 and 2 g, such as between 0.5 and 1.5 g of said Zoledronic acid or pharmaceutically acceptable salt thereof.
- compositions described may comprise anti-microbial agents, such as antibiotics. Said agents may be released from the composition in vivo and therefore prevent, limit or treat infection in the treated subject.
- antibiotics include natural antibiotics as well as other semisynthetic and synthetic antibacterial or bacteriostatic compounds, which are acting against pathogenic and/or infectious microorganisms, e.g. staphylococci.
- antibiotics which can be used with the invention includes fosfomycin, gentamicin, tetracycline-HCI, vancomycin, Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin,Tobramycin, Paromomycin, Streptomycin, Spectinomycin, Geldanamycin, Herbimycin, Rifaximin, Loracarbef, Ertapenem, Doripenem, Imipenem/Cilastatin, Meropenem, Cefadroxil, Cefazolin, Cefalotin or Cefalothin, Cefalexin, Cefaclor, Cefamandole, Cefoxitin, Cefprozil, Cefuroxime, Cefixime, Cefdinir, Ce
- the antibiotic is selected from the group consisting of fosfomycin, gentamicin, tetracycline, vancomycin, tobramycin, gentamycin, cephalosporin and a combination thereof.
- the at least one bioactive agent comprises or consists of fosfomycin or a pharmaceutically acceptable salt thereof.
- the bone reconstruction composition comprises at least 80 mg/ml of fosfomycin, such as at least 97 mg/ml, such as at least 110 mg/ml, and up to 200 mg/ml, such as up to 175 mg/ml of fosfomycin or pharmaceutically acceptable salt thereof, where ml refers to the final volume of the composition.
- the biocompatible carrier comprises an osteoconductive material such as hydroxyapatite and at least one bioactive agent, such as fosfomycin or a pharmaceutically acceptable salt thereof.
- the biocompatible carrier comprises an osteoconductive material such as hydroxyapatite and a bisphosphonate, such as Zoledronic acid, and at least another bioactive agent, such as fosfomycin or a pharmaceutically acceptable salt thereof.
- fosfomycin accelerates curing of a composition comprising hydroxyapatite and may improve mechanical stability of said composition in-situ.
- the bone reconstruction composition may also comprise a cytostatic agent.
- Cytostatic agents such as Bendamustine, Busulfan, Carmustine, Chlorambucil, Cyclophosphamide, dacarbazine, Ifosfamide, Melphalan, Procarbazine, Streptozocin and Temozolomide or derivatives thereof may thus also be comprised in the bone reconstruction composition.
- the bone reconstruction composition can in a similar way comprise an antiviral compound, an antifungal compound, a tuberculostatic or tuberculocidal compound or an antiparasite compound or a genetically altered variant of the aforementioned for the purpose of targeted antitumor treatment.
- Another additive, which may be included in the bone reconstruction composition, is a non-ionic X- ray contrast agent.
- the antibiotic agent may be present within the composition in any suitable amount.
- at least 80 mg/ml such as at least 97 mg/ml, such as at least 110 mg/ml, and up to 200 mg/ml, such as up to 175 mg/ml of said antibiotic or antibiotic mixture, where ml refers to the final volume of the composition.
- antimicrobial/anti-biofilm agents may be comprised in the bone reconstruction composition to complement each other and deliver synergistic antimicrobial effects to the site of the bone defect.
- Said bioactive agents will spread into the biocompatible matrix e.g. the bone graft material as well as into the area around the bone defect, e.g. into local hematoma and/or seroma by way of elution and diffusion from the composite.
- non-antibiotic compounds with innate antibacterial properties, such as silver and copper; N-acetylcysteine; nitric oxide (NO)-releasing coatings with diazeniumdiolates or calcium peroxide; bioactive antibacterial coatings; antimicrobials able to bypass the biofilm barrier, such as Daptomycin or, Minocycline; peptides such as human ⁇ -defensin-3; cyclic di-GMP modulating proteins; the transcriptional regulatory protein MucR; nanostructured compounds such as silver or chitosan; enzymes that lyse certain elements of the biofilm e.g. dispersin B or proteinase K.
- non-antibiotic compounds with innate antibacterial properties, such as silver and copper; N-acetylcysteine; nitric oxide (NO)-releasing coatings with diazeniumdiolates or calcium peroxide; bioactive antibacterial coatings; antimicrobials able to bypass the biofilm barrier, such as Daptomycin or, Min
- cytotoxic agents which are described in detailed above, have been found to be successful in removing biofilms from implant surfaces.
- citric acid was found to be successful in eliminating biofilms from titanium surfaces.
- a list of other agents that inhibit biofilm formation is found in Rabin N et al. ( Rabin N, Zheng Y, Opoku-Temeng C, Du Y, Bonsu E and Sintim HO, Future Medicinal Chemistry, 2015 , 7(5):647-671 ).
- the bone reconstruction compositions described by the present invention may comprise agents that stimulate and/or accelerate bone formation (also referred to as "growth promoting agents"), such as osteoinductive agents, growth factors and hormones. Specific signaling molecules, growth factors and derivatives thereof, which are locally acting are preferred. Said agents may be released from the composition in vivo.
- biocompatible carrier of the present disclosure is also an effective delivery vehicle for bioactive agents such as growth factors and antiresorptive agents.
- the bone reconstruction composition may comprise at least one growth or differentiation factor selected from the group consisting of bone morphogenic proteins (BMPs), members of the TGF-superfamily, platelet-derived growth factor (PDGF), fibroblast growth factors (FGFs), insulin-like growth factors (IGFs), metalloproteinases, vascular endothelial growth factor (VEGFs A, B, C or D), angioprotein 1 and 2, and combinations thereof.
- BMPs bone morphogenic proteins
- PDGF platelet-derived growth factor
- FGFs fibroblast growth factors
- IGFs insulin-like growth factors
- VEGFs A, B, C or D vascular endothelial growth factor
- angioprotein 1 and 2 angioprotein 1 and 2, and combinations thereof.
- the growth promoting or osteoinductive agent is a bone morphogenic protein (BMP, for example the growth promoting agent may be selected from the group consisting of BMP1, BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8a, BMP8b, BMP10, BMP15 and a combination thereof.
- BMPs are BMPs of the same species to be treated with the bone reconstruction composition.
- the BMP may be human BMP, for example the growth promoting agent may be selected from the group consisting of human BMP1, human BMP2, human BMP3, human BMP4, human BMP5, human BMP6, human BMP7, human BMP8a, human BMP8b, human BMP10, human BMP15 and a combination thereof.
- human BMP refers to wild type human BMP.
- growth promoting agents examples include parathyroid hormones and derivatives thereof, estrogens, progesterone, androgens, testosterones, calcitonin, somatomedin, and oxytocin, preferably also autologous, but they can also be produced according to procedures known within the art.
- the bone reconstruction compositions described by the present disclosure comprise at least one bioactive agent e.g. a biologically and/or therapeutically active agent, also referred to as bioactive agent.
- a bioactive agent e.g. a biologically and/or therapeutically active agent, also referred to as bioactive agent.
- other bioactive agents may be comprised in the composition, as described here below.
- the at least one bioactive agent comprises or consists of a BMP antagonist inhibitors selected from the group consisting of noggin, chordin, sclerostin, follostatin.
- the at least one bioactive agent comprises or consists of a BMP antagonist inhibitors selected from the group consisting of members of the DAN family, for example sclerostin, members of the twisted gastrulation family and noggin/chordin.
- the at least one bioactive agent comprises or consists of a signaling protein, for example a signaling protein selected from the group consisting of Wnt proteins, lymphoid enhancer-binding factor 1 (Lef1), ⁇ -catenin, parathyroid hormone-related protein (PTHrP), colony stimulating factors, Indian hedgehog homolog (IHH), Hypoxia-inducible factor 1-alpha (HIF- ⁇ ) and combinations thereof.
- a signaling protein selected from the group consisting of Wnt proteins, lymphoid enhancer-binding factor 1 (Lef1), ⁇ -catenin, parathyroid hormone-related protein (PTHrP), colony stimulating factors, Indian hedgehog homolog (IHH), Hypoxia-inducible factor 1-alpha (HIF- ⁇ ) and combinations thereof.
- osteogenesis involves active participation of various types of cells, including osteoblasts, chondroblasts, osteocytes and osteoclasts.
- Bone formation is the result of successful recruitment and differentiation of locally available and/or implanted pluripotent progenitor cells into mature bone matrix producing cells at the site of the lesion.
- Suspensions of pluripotent mesenchymal stem cells (MSC's) and/or platelet rich plasma (PRP) can be harvested form a variety of sources (e.g. blood, bone marrow and/or adipose tissue), incorporated into an appropriate biocompatible carrier, preferably comprising an osteoconductive material, and thus delivered to the site of a bone defect as part of the method disclosed herein.
- sources e.g. blood, bone marrow and/or adipose tissue
- tumor infiltrating lymphocytes could be incorporated in a similar fashion into a surgically treated bone tumor site, to allow local delivery of cells for specific purposes, such as the killing of tumor cells, which may enhance local recurrence rates.
- the at least one bioactive agent comprises or consists of a human cell suspension, for example a human cell suspension comprising or consisting of mesenchymal stem cells and/or lymphocytes and/or platelet depleted plasma and/or lipoaspirate of autogenic or allogenic origin such as the stromal vascular fraction.
- cell suspensions are added to or substitute part of the solvent comprised in the biocompatible carrier.
- brachytherapy radioactive isotopes are sealed in tiny pellets or "seeds" which can be delivered to patients using delivery devices, e.g. an appropriate biocompatible carrier, such as a carrier comprising an osteoconductive material.
- delivery devices e.g. an appropriate biocompatible carrier, such as a carrier comprising an osteoconductive material.
- an appropriate biocompatible carrier such as a carrier comprising an osteoconductive material.
- the isotopes decay naturally, they give off radiation that damage nearby cancer cells. If left in place, after a few weeks or months, depending on the isotope, the isotopes decay completely and no longer give off radiation.
- the seeds will not cause harm if they are left in the body.
- Brachytherapy may be able to deliver higher doses of radiation to some sites than external-beam radiation therapy while causing less damage to normal tissue.
- the seeds can be resorbable or non-resorbable.
- brachytherapy sources can be temporary or permanent. These particles or seeds may be also embedded into the biocompatible matrix.
- these solid particles are embedded into the biocompatible carrier.
- the at least one bioactive agent comprises or consists of a radioactive material, for example a radioactive material selected from the group consisting of Cesium-131 or Cesium-137 or Cobalt-60 or Iridium-192 or lodine-125 or Palladium-103 or Ruthenium-106 or Radium-226 and combinations thereof.
- a radioactive material selected from the group consisting of Cesium-131 or Cesium-137 or Cobalt-60 or Iridium-192 or lodine-125 or Palladium-103 or Ruthenium-106 or Radium-226 and combinations thereof.
- the at least one bioactive agent comprises or consists of a cytokine, for example a cytokine selected from the group consisting of interleukin-1 (IL-1) or interleukin-6 (IL-6) or tumor necrosis factor alpha (TNF-alpha) or receptor activator of nuclear factor kappa-B ligand (RANKL) or core-binding factor alpha 1 (cbfa1) or osteogenin or SMADs proteins 1-8 or osteogenic growth peptide (OGP) and combinations thereof.
- IL-1 interleukin-1
- IL-6 interleukin-6
- TNF-alpha tumor necrosis factor alpha
- RTKL nuclear factor kappa-B ligand
- cbfa1 core-binding factor alpha 1
- the biocompatible carrier comprises a solvent, for example a solvent selected from the group consisting of water, simple sugars such as for example glucose, fructose, mannitol, a contrast agent such as iohexol, platelet depleted plasma, lipoaspirate, fosfomycin, vancomycin or gentamycin and combinations thereof.
- a solvent for example a solvent selected from the group consisting of water, simple sugars such as for example glucose, fructose, mannitol, a contrast agent such as iohexol, platelet depleted plasma, lipoaspirate, fosfomycin, vancomycin or gentamycin and combinations thereof.
- the at least one bioactive agent comprises or consists of an antiadhesive agent, for example monomeric trimethylsilane (TMS) or nonionic surfactants, e.g Pluronic F127.
- an antiadhesive agent for example monomeric trimethylsilane (TMS) or nonionic surfactants, e.g Pluronic F127.
- the at least one bioactive agent may be an antimetabolite, a chemical that inhibits the use of a metabolite which is part of the normal metabolidm of the subject.
- the antimetabolite is selected from the group consisting of Asparaginase, Capecitabine, Cytarabine, 5- Fluoro Uracil, Fludarabine, Gemcitabine, Methotrexate, Pemetrexed and Raltitrexed.
- the at least one bioactive agent may be an anti-tumour antibiotic selected from a group composed of Actinomycin D / Dactinomycin, Bleomycin, Daunorubicin, Doxorubicin, Doxorubicin (pegylated liposomal), Epirubici, Idarubicin, Mitomycin and Mitoxantrone.
- bioactive agents e.g. biologically and/or therapeutically active agents, may be plant alkaloids/ microtubule inhibitors selected from a group composed of Etoposide, Docetaxel, Irinotecan, Paclitaxel, Topotecan, Vinblastine, Vincristine and Vinorelbine.
- the at least one bioactive agent may be a DNA linking agent including Carboplatin, Cisplatin and Oxaliplatin.
- the at least one bioactive agent may be a hormons including Anastrozole, Abiraterone, Amifostine, Bexarotene, Bicalutamide, Buserelin, Cyproterone, Degarelix, Exemestane, Flutamide, Folinic acid, Fulvestrant, Goserelin, Lanreotide, Lenalidomide, Letrozole, Leuprorelin, Medroxyprogesterone, Megestrol, Mesna, Octreotide, Stilboestrol and Tamoxifen.
- a hormons including Anastrozole, Abiraterone, Amifostine, Bexarotene, Bicalutamide, Buserelin, Cyproterone, Degarelix, Exemestane, Flutamide, Folinic acid, Fulvestrant, Goserelin, Lanreotide, Lenalidomide, Letrozole, Leuprorelin, Medroxyprogesterone, Megestrol
- kit-of-parts and the methods for treatment of a bone defect described in the present invention comprise a biocompatible matrix e.g. a bone graft material comprising solid particles of natural origin. Also compositions of the invention may comprise a biocompatible matrix.
- said particles comprise or consist of cancellous bone.
- said particles comprise of consist of a bone graft material, e.g. a bone graft material as described below.
- the presence of solid particles and/or scaffolds in the biocompatible matrix adds mechanical stability to the bone reconstruction composition and diminishes the risk of premature loss of mechanical stability, liquefaction and/or resorption of the bone reconstruction composition.
- the particles of the biocompatible matrix preferably have a particle size of at least 0.5 mm, such as at least 1 mm, such as at least 2 mm, such as at least 3 mm.
- Said particles may have any shape, they can for example be diamonds, spheres or cubes.
- the biocompatible matrix comprises or consists of a bone graft material.
- the methods may comprise impacting a damaged bone with the bone reconstruction composition and biocompatible matrix components such as said bone graft material and/or synthetic particles.
- the bone graft material comprises bone from a human or non-human animal. It is preferred that the bone graft material comprises bone from the same species, as the species to be treated with the bone graft material. Thus, frequently it is preferred that said bone graft material comprises bone from a human being.
- the bone graft material consists of bone from a human or non-human animal.
- the bone graft material may consist of human bone.
- Said bone graft material may be autogenic or allogenic bone, i.e. the bone graft material may comprise or consist of bone from the individual to be treated, or it may comprise or consist of bone from another individual of the same species, or a combination of both.
- the biocompatible matrix e.g. a bone graft material
- the biocompatible matrix comprises particles of cancellous bone, wherein the cancellous bone is allograft and/or autograft.
- the biocompatible matrix e.g. the bone graft material may essentially consist of cancellous bone, i.e. at least 70%, preferably 80%, such as at least 85% of the biocompatible matrix consists of cancellous bone, for example human cancellous bone.
- the remainder of the biocompatible matrix may consist of remnants of material naturally associated with cancellous bone, for example cortical bone, soft tissues of bone, lipids and/or blood.
- the cancellous bone comprises no more than 10% water and no more than 5% lipids.
- said bone graft material comprises demineralized bone matrix.
- said bone graft material comprises between 1 and 10 ml of demineralized bone matrix.
- said bone graft material comprises between 1 and 10 g of demineralized bone matrix.
- said bone graft material is allograft and/or autograft bone, for example vascularized autograft.
- said bone, e.g. cancellous bone is present in the biocompatible matrix e.g. in the bone graft material in the form of smaller particles, for example in particles having a particle size of no more than 5 mm, such as no more than 4 mm, for example no more than 3 mm, for example in the range of 2 to 3 mm.
- the bone, e.g. cancellous bone may be present in the bone graft material in the form of smaller particles having a size in the range of -3.5 to -6 mesh, for example in the range of -4 to -6 mesh, such as in the range of -5 to -6 mesh.
- a "-" before the sieve mesh indicates the particles pass through the sieve. Thus, by way of example if a material is described as -6 mesh, then 90% or more of the material will pass through a 6-mesh sieve.
- Said bone e.g. cancellous bone may undergo processing that may comprise fragmenting the material, cleaning the material and/or disinfecting the material before it is ready for use as a biocompatible matrix.
- Said bone in the form of particles may be prepared by milling, crushing or other mean of fragmentation.
- the bone in the form of particles may be prepared using a bone mill or a device having the same function.
- said biocompatible matrix e.g. bone graft material is frozen cancellous allograft bone taken from a hospital bone bank and stored as per the routine procedure of the hospital.
- Such material may be devoid of cortical and soft tissue remnants.
- said biocompatible matrix e.g. bone graft material is autograft bone, wherein said bone is cancellous autograft or corticocancellous autograft shaped and applied into the outer surface areas of an individual bone defect in the area of a cortical window.
- longer curing time and more compression during curing may apply due to the higher content of blood and other liquids typically present in autograft material.
- said biocompatible matrix e.g. bone graft material comprises cells capable of true osteogenesis.
- RIA autograft Reamer-Irrigator-Aspirator technique
- said composition used is cured to allow setting.
- improved interdigitation with host bone and biocompatible matrix e.g. bone graft material
- the curing procedure may be performed for few minutes and/or until complete setting.
- the bone reconstruction composition cures in a time range of 2 to 60 minutes after all ingredients of said composition are mixed.
- the curing time may vary, it can for example be 2 to 50 minutes, preferably 2 to 40 minutes, preferably 2 to 30 minutes, preferably 2 to 20 minutes, preferably 2 to 10 minutes, preferably 2 to 5 minutes, preferably 2 to 3 minutes.
- the bone reconstruction composition thickens to a paste in a time range of 2 to 10 minutes after all ingredients of said composition are mixed, such as in a time range of 2 to 8 minutes, such as in a time range of 2 to 7 minutes, such as in a time range of 2 to 6 minutes, such as in a time range of 2 to 5 minutes, such as in a time range of 2 to 3 minutes after all ingredients of said composition are mixed.
- a composition to be used together with bone graft material for treatment of bone defect is prepared.
- the bone reconstruction composition may be prepared by any useful method.
- the bone reconstruction composition may be prepared by a method comprising the steps of:
- the bioactive agents are provided in a solvent.
- additional solvent is added to the mixture, said solvent being free from bioactive agents or comprising one or more bioactive agents.
- the solvent may be any useful solvent e.g. water.
- Said water may comprise additives, such as a buffer, a salt and/or other components e.g. mannitol.
- the solvent may be a buffered saline aqueous solution, e.g. a citrate buffered aqueous solution comprising a physiological level of salt, e.g. in the range of 0-7 to 1.0%, such as approximately 0.9% NaCl.
- composition comprises the following steps:
- the composition may comprise at least 50% of HA and calcium sulfate.
- the composition may also comprise at least 0.3 mg/ml of ZA, preferably approximately 0.55 mg/ml and up to 0.80 mg/ml, where ml refers to the final volume of the composition.
- a longer setting time is allowed, so that the composition reaches a harder consistency.
- the resulting mould is applied directly without the help of a syringe.
- one or more bioactive agents are added to the composition.
- Some bioactive agents are in liquid forms and are added to the composition as they are. Some bioactive agents are not in liquid form and thus they are first mixed with a solvent and dissolved, and only after they are added to the mixture.
- Bioactive agents In the sections above "Bioactive agents”, “Bisphosphonate”, Antimicrobial agents”, “Growth promoting agents” and” Other bioactive agents” there are details regarding the various types of agents can be beneficially be added to the composition.
- an antibiotic is added to said composition.
- the antibiotic may be mixed with a suitable solvent prior to its addition to the composition.
- the dissolved antibiotic may be added into the mixing device containing BGS prior to addition of zolendric acid.
- the dissolved antibiotic may be added into the mixing device containing BGS after addition of zolendric acid.
- the composition may comprise at least 80 mg/ml, such as at least 97 mg/ml, such as at least 110 mg/ml, and up to 175 mg/ml of said antibiotic or antibiotic mixture, where ml refers to the final volume of the composition.
- Another example of a useful method to prepare composition comprises the following steps:
- the antibiotic added is fosfomycin.
- the antibiotic gentamicin or vancomycin is added. Additional anti-microbial agents may be added as described in the section "Antibiotic”.
- Methods are described for treatment of a bone defect in a subject, said treatment comprising providing a biocompatible carrier, providing biocompatible matrix, e.g. a bone graft material, and providing impacting a bone defect with said biocompatible carrier and said biocompatible matrix in alternate layers to achieve a mechanically stable bone reconstruction construct, as described in the detail in the section above "Treatment of bone defects".
- a biocompatible carrier providing biocompatible matrix, e.g. a bone graft material
- biocompatible matrix e.g. a bone graft material
- the bone reconstruction composition typically contains the bioactive agents, it is applied over the entire surface of all relevant areas of the individual defect and in direct contact with the local host bone. Then, the biocompatible matrix is impacted in the bone defect applying a certain pressure. This layer is covered by impacting said composition comprising one or more bioactive agents over it. This second layer may also be covered with further biocompatible matrix. This third layer may be further covered with said composition comprising one or more bioactive agents. The procedure is repeated until the desired level of defect fill is achieved. Impacting the reconstruction construct within said bone defect with said composition and said biocompatible matrix during or at the end of the reconstruction process can contribute to achieve a denser and more mechanically stable bone reconstruction construct.
- Bone defect reconstruction may require additional mechanical stabilization with appropriate internal or external bone fixation devices including but not limited to standard or custom wires, pins, screws, plates, nails, prosthetic- and/or external fixation devices, but also auto- or allograft bone with- or without vascularized bone grafts, which can help reinforcing the structure of the defected bone.
- appropriate internal or external bone fixation devices including but not limited to standard or custom wires, pins, screws, plates, nails, prosthetic- and/or external fixation devices, but also auto- or allograft bone with- or without vascularized bone grafts, which can help reinforcing the structure of the defected bone.
- said method comprises forming at least 2 layers, one comprising the biocompatible matrix and one comprising the bone reconstruction composition, so that the bone defect is repaired.
- said method comprises forming at least 3 layers, such as at least 4 layers, such as at least 5 layers, such as at least 6 layers, wherein at least one comprises the biocompatible matrix and at least one comprises the composition, so that the bone defect is repaired.
- the present disclosure relates to a method for bone reconstruction in an individual suffering from a bone defect, said method comprising performing the method as described herein, thereby obtaining growth of healthy bone on the site of the bone defect in said individual.
- Sequential imaging demonstrated progressive consolidation of the inserted graft material without any evidence of persistent osteolysis or local recurrence. Rapid and homogeneous remodeling typically started in well-contained areas with cancellous bone contact. Substantial bone formation was also observed in uncontained areas where graft material had been applied to the surface of metallic implants or surrounding cortical bone in some cases.
- Rapid and homogeneous remodeling typically started in areas with cancellous bone contact in the periphery of the defects but was not limited to the cavities only. Substantial periosteal bone formation was also observed in areas of ungrafted surrounding cortical bone.
- x-rays taken prior treatment, right after and few months after treatment show bone formation and remodeling in 6 different patients.
- the treatment represented in figures 1-6 and 10 was performed by applying a biocompatible matrix, e.g. cancellous allograft, and a bone reconstruction composition, e.g. bone graft substitute (BGS) comprising zoledronic acid and they all show new bone formation and remodeling at 3 weeks to 6 months after treatment.
- BGS bone graft substitute
- the treatment represented in figure 7 instead, was performed by applying only a bone reconstruction composition, e.g. the bone graft substitute (CeramentTM
- a bone reconstruction composition e.g. the bone graft substitute (CeramentTM
- complete disappearance of the bone graft substitute is observed 6 months after the treatment.
- the patient represented in figure 8 was affected by aseptic loosening of an intercalary diaphyseal replacement in the right femur, treated with 2 stage revision and intermediate implantation of an antibiotic cement spacer and re-implantation of a new, cemented, silver coated intercalary spacer and periprosthetic bone defect reconstruction.
- Part of the bone defect was filled using a biocompatible matrix, e.g.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Dermatology (AREA)
- Animal Behavior & Ethology (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Transplantation (AREA)
- Epidemiology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Botany (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Zoology (AREA)
- Materials For Medical Uses (AREA)
Claims (11)
- Härtbare Knochenrekonstruktions-Zusammensetzung, umfassend Calciumsulfat und/oder Calciumphosphat, ein antiresorptives Mittel und Fosfomycin, wobei das antiresorptive Mittel ein Bisphosphonat umfasst oder aus einem Bisphosphonat besteht.
- Knochenrekonstruktions-Zusammensetzung nach Anspruch 1, wobei das Calciumphosphat ein Hydroxylapatit umfasst oder aus diesem besteht.
- Zusammensetzung, umfassend• eine Knochenrekonstruktions-Zusammensetzung, die einen biokompatiblen Träger und zwei oder mehr bioaktive Wirkstoffe umfasst,
wobei der biokompatible Träger Calciumsalze, Hydroxylapatit und natürliche und/oder synthetische Polymere umfasst;
wobei mindestens einer der bioaktiven Wirkstoffe die Aushärtung der Zusammensetzung beschleunigt und wobei mindestens einer der bioaktiven Wirkstoffe die Aushärtung der Zusammensetzung verlangsamt;
wobei der bioaktive Wirkstoff, der die Aushärtung der Zusammensetzung beschleunigt, Fosfomycin ist,
und• eine biokompatible Matrix aus festen Partikeln natürlichen Ursprungs;
wobei die Partikel der biokompatiblen Matrix Knochentransplantatmaterial umfassen oder daraus bestehen und/oder die Partikel der biokompatiblen Matrix Partikel aus spongiösem Knochen umfassen; und wobei der spongiöse Knochen entmineralisierte Knochenmatrix (DBM) umfasst. - Zusammensetzung nach Anspruch 3, wobei der bioaktive Wirkstoff, der die Aushärtung der Zusammensetzung verlangsamt, ein Bisphosphonat ist.
- Kit-of-Parts, umfassend:• eine Knochenrekonstruktions-Zusammensetzung nach Anspruch 3 oder 4, und• eine biokompatible Matrix nach Anspruch 3.
- Zusammensetzung zur Verwendung bei der Behandlung eines Knochendefekts bei einem Individuum, das diese benötigt, wobei die Zusammensetzung umfasst oder besteht aus• einer Knochenrekonstruktions-Zusammensetzung nach Anspruch 3 oder 4, und• einer biokompatiblen Matrix nach Anspruch 3,und wobei die Behandlung das Aufbringen der Knochenrekonstruktions-Zusammensetzung und der biokompatiblen Matrix auf den Knochendefekt durch Einspritzen und/oder Ausformen umfasst, wobei die Knochenrekonstruktions-Zusammensetzung und die biokompatible Matrix in mindestens 2 abwechselnden Schichten, wie beispielsweise mindestens 4 abwechselnden Schichten, wie beispielsweise mindestens 6 abwechselnden Schichten, impaktiert werden, wobei mindestens eine Schicht die Knochenrekonstruktions-Zusammensetzung umfasst oder aus dieser besteht und mindestens eine Schicht die biokompatible Matrix umfasst oder aus dieser besteht.
- Zusammensetzung nach einem der vorhergehenden Ansprüche, wobei die Partikel der biokompatiblen Matrix eine Partikelgröße von mindestens 0,5 mm, wie beispielsweise mindestens 1 mm, wie beispielsweise mindestens 2 mm, wie beispielsweise mindestens 3 mm, aufweisen.
- Zusammensetzung nach einem der vorhergehenden Ansprüche, wobei die Partikel der biokompatiblen Matrix eine Partikelgröße von nicht mehr als 20 mm, wie beispielsweise nicht mehr als 15 mm, wie beispielsweise nicht mehr als 10 mm, wie beispielsweise nicht mehr als 5 mm, aufweisen.
- Zusammensetzung nach einem der vorhergehenden Ansprüche, wobei die biokompatible Matrix Partikel aus spongiösem Knochen umfasst und wobei der spongiöse Knochen nicht mehr als 10 % Wasser und nicht mehr als 5 % Lipide umfasst.
- Zusammensetzung nach einem der vorhergehenden Ansprüche, wobei die Knochenrekonstruktions-Zusammensetzung in einem Zeitbereich von 2 bis 60 Minuten aushärtet, nachdem alle Bestandteile der Zusammensetzung gemischt wurden.
- Zusammensetzung nach einem der vorhergehenden Ansprüche, wobei die Knochenrekonstruktions-Zusammensetzung in einem Zeitbereich von 2 bis 10 Minuten zu einer Paste härtet, nachdem alle Bestandteile der Zusammensetzung gemischt wurden.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP20212234.7A EP3821917A1 (de) | 2015-10-05 | 2016-10-04 | Zusammensetzungen und verfahren zur behandlung von knochendefekten |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DKPA201570626 | 2015-10-05 | ||
PCT/DK2016/050320 WO2017059863A1 (en) | 2015-10-05 | 2016-10-04 | Compositions and methods for treatment of bone defects |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP20212234.7A Division EP3821917A1 (de) | 2015-10-05 | 2016-10-04 | Zusammensetzungen und verfahren zur behandlung von knochendefekten |
Publications (2)
Publication Number | Publication Date |
---|---|
EP3359209A1 EP3359209A1 (de) | 2018-08-15 |
EP3359209B1 true EP3359209B1 (de) | 2020-12-09 |
Family
ID=55023819
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP16788416.2A Active EP3359209B1 (de) | 2015-10-05 | 2016-10-04 | Zusammensetzungen und verfahren zur behandlung von knochendefekten |
EP20212234.7A Pending EP3821917A1 (de) | 2015-10-05 | 2016-10-04 | Zusammensetzungen und verfahren zur behandlung von knochendefekten |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP20212234.7A Pending EP3821917A1 (de) | 2015-10-05 | 2016-10-04 | Zusammensetzungen und verfahren zur behandlung von knochendefekten |
Country Status (4)
Country | Link |
---|---|
US (2) | US20180289859A1 (de) |
EP (2) | EP3359209B1 (de) |
DK (1) | DK3359209T3 (de) |
WO (1) | WO2017059863A1 (de) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3359209B1 (de) | 2015-10-05 | 2020-12-09 | Hettwer Holding ApS | Zusammensetzungen und verfahren zur behandlung von knochendefekten |
AU2021311459A1 (en) | 2020-07-21 | 2023-02-02 | Shankar Rajeswaran M.D. Llc | System and method for treatment of bone |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040157798A1 (en) | 2001-04-03 | 2004-08-12 | Little David Graham | Drug for use in bone grafting |
WO2014128217A1 (en) | 2013-02-20 | 2014-08-28 | Bone Support Ab | Improved setting of hardenable bone substitute |
US20150283291A1 (en) | 2014-04-02 | 2015-10-08 | Heraeus Medical Gmbh | Fosfomycin preparation, a method for producing the preparation, and a polymethylmethacrylate bone cement powder containing the preparation |
US9180137B2 (en) | 2010-02-09 | 2015-11-10 | Bone Support Ab | Preparation of bone cement compositions |
WO2017059863A1 (en) | 2015-10-05 | 2017-04-13 | Hettwer Holding Aps | Compositions and methods for treatment of bone defects |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5366507A (en) * | 1992-03-06 | 1994-11-22 | Sottosanti John S | Method for use in bone tissue regeneration |
WO2007068489A2 (en) * | 2005-12-14 | 2007-06-21 | Scil Technology Gmbh | A moldable biomaterial for bone regeneration |
WO2009036279A1 (en) * | 2007-09-14 | 2009-03-19 | Purdue Research Foundation | Demineralized cancellous bone scaffolds |
US20110137417A1 (en) * | 2009-12-04 | 2011-06-09 | Transplant Technologies of Texas | Multiple wafer cortical bone and cancellous bone allograft with cortical pins |
US9283866B2 (en) * | 2012-01-31 | 2016-03-15 | Joy MM Deleware, Inc. | Overhead power grid for mobile mining machines |
US10006705B2 (en) * | 2015-02-09 | 2018-06-26 | Warsaw Orthopedic, Inc. | Methods for treating tissue materials |
-
2016
- 2016-10-04 EP EP16788416.2A patent/EP3359209B1/de active Active
- 2016-10-04 US US15/765,759 patent/US20180289859A1/en active Pending
- 2016-10-04 EP EP20212234.7A patent/EP3821917A1/de active Pending
- 2016-10-04 DK DK16788416.2T patent/DK3359209T3/da active
- 2016-10-04 WO PCT/DK2016/050320 patent/WO2017059863A1/en active Application Filing
-
2021
- 2021-05-11 US US17/317,540 patent/US20210402058A1/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040157798A1 (en) | 2001-04-03 | 2004-08-12 | Little David Graham | Drug for use in bone grafting |
US9180137B2 (en) | 2010-02-09 | 2015-11-10 | Bone Support Ab | Preparation of bone cement compositions |
WO2014128217A1 (en) | 2013-02-20 | 2014-08-28 | Bone Support Ab | Improved setting of hardenable bone substitute |
US20150283291A1 (en) | 2014-04-02 | 2015-10-08 | Heraeus Medical Gmbh | Fosfomycin preparation, a method for producing the preparation, and a polymethylmethacrylate bone cement powder containing the preparation |
WO2017059863A1 (en) | 2015-10-05 | 2017-04-13 | Hettwer Holding Aps | Compositions and methods for treatment of bone defects |
Non-Patent Citations (9)
Title |
---|
ANONYMOUS: "CERAMENT G- Instruction for use", A 0450-01, 0000, pages 1 - 7, XP055843466 |
ANONYMOUS: "CERAMENT G Mixing chart", pages 1, XP055843479 |
ANONYMOUS: "CERAMENT G Product fact sheet", BONESUPPORT, PR 0935-02, October 2020 (2020-10-01), pages 1 - 2, XP055843487 |
Communication pursuant to Article 94(3) EPC- Applicant Hettwer Holding ApS- 30 August 2019 (2019-08-30) |
GINEBRA MARIA PAU, TANIA TRAYKOVA, JOSEP A. PLANELL: "Calcium phosphate cements: Competitive drug carriers for the musculoskeletal system?", BIOMATERIALS, vol. 27, no. 10, 1 April 2006 (2006-04-01), pages 2171 - 2177, XP027950926 |
LIDEN E., EDVINSSON J.: "Summary of extra tests performed linked to Hettwer Annex A", BONESUPPORT, 26 August 2021 (2021-08-26), pages 1 - 6, XP055843475 |
PCT/DK2016/050320 - Demand for Preliminary Examination- 7 August 2017 (2017-08-07) |
Repeat preparation and test in WO 2017/059863: "Tests with ZA and Fosfomycin added to a ceramic bone substitute", BONESUPPORT, pages 1 - 4 |
RICHELSOPH KELLY C., WEBB NATHAN D., HAGGARD WARREN O.: "Elution Behavior of Daptomycin-loaded Calcium Sulfate Pellets", CLINICAL ORTHOPAEDICS AND RELATED RESEARCH, no. 461, August 2007 (2007-08-01), pages 68 - 73, XP055843460 |
Also Published As
Publication number | Publication date |
---|---|
US20210402058A1 (en) | 2021-12-30 |
EP3359209A1 (de) | 2018-08-15 |
WO2017059863A1 (en) | 2017-04-13 |
US20180289859A1 (en) | 2018-10-11 |
DK3359209T3 (en) | 2021-03-15 |
EP3821917A1 (de) | 2021-05-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Jiménez et al. | Bibliographic review on the state of the art of strontium and zinc based regenerative therapies. Recent developments and clinical applications | |
Wang et al. | Bone grafts and biomaterials substitutes for bone defect repair: A review | |
Ferguson et al. | Ceramic biocomposites as biodegradable antibiotic carriers in the treatment of bone infections | |
Thomas et al. | Calcium sulfate: Properties and clinical applications | |
Verron et al. | Calcium phosphate biomaterials as bone drug delivery systems: a review | |
EP2608778B1 (de) | Zusammensetzungen und verfahren zur behandlung von knochendefekten | |
US20210402058A1 (en) | Compositions and methods for treatment of bone defects | |
JP2006519082A (ja) | 新代用骨組成物 | |
US20130121956A1 (en) | Composition for Enhancing Bone Formation | |
US7887831B2 (en) | Bone enhancing composite | |
US9180137B2 (en) | Preparation of bone cement compositions | |
AU2014331971B2 (en) | Processed bone particle compositions and related methods | |
Simpson et al. | Synergistic use of biomaterials and licensed therapeutics to manipulate bone remodelling and promote non-union fracture repair | |
JP2024037985A (ja) | 人工骨膜 | |
Fernandes et al. | Calcium sulfate as a scaffold for bone tissue engineering: a descriptive review | |
Yang et al. | Biodegradable magnesium incorporated microspheres enable immunomodulation and spatiotemporal drug release for the treatment of osteonecrosis of the femoral head | |
US20220287972A1 (en) | Treatment approach by targeted delivery of bioactive molecules | |
Daculsi et al. | The micro macroporous biphasic calcium phosphate concept for bone reconstruction and tissue engineering | |
Wang et al. | Bone grafts and bone substitutes for bone defect management | |
US20110288652A1 (en) | Materials and methods for treating critically sized defects in mouse bone | |
WO2004043333A2 (en) | Bone enhancing composite | |
US20220118157A1 (en) | Method for bone healing or treatment of bone fracture | |
WO2024026121A1 (en) | Adhesive compositions with tunable porosity and acidity content and methods of use thereof | |
El-Messiry | Comparative Study on the Effect of Nano-hydroxyapatite and Theobromine on Healing of Extraction Socket in Albino Rats (Histological and Immuno-Histochemical Study)’ | |
Han et al. | Minimally Invasive Implantable Biomaterials for Bone Reconstruction |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: UNKNOWN |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20180507 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
AX | Request for extension of the european patent |
Extension state: BA ME |
|
DAV | Request for validation of the european patent (deleted) | ||
DAX | Request for extension of the european patent (deleted) | ||
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
17Q | First examination report despatched |
Effective date: 20190830 |
|
TPAC | Observations filed by third parties |
Free format text: ORIGINAL CODE: EPIDOSNTIPA |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: GRANT OF PATENT IS INTENDED |
|
INTG | Intention to grant announced |
Effective date: 20200605 |
|
GRAS | Grant fee paid |
Free format text: ORIGINAL CODE: EPIDOSNIGR3 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE PATENT HAS BEEN GRANTED |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: REF Ref document number: 1342718 Country of ref document: AT Kind code of ref document: T Effective date: 20201215 Ref country code: CH Ref legal event code: EP |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R096 Ref document number: 602016049500 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: T3 Effective date: 20210310 Ref country code: CH Ref legal event code: NV Representative=s name: MICHELI AND CIE SA, CH |
|
REG | Reference to a national code |
Ref country code: SE Ref legal event code: TRGR |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210310 Ref country code: FI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20201209 Ref country code: RS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20201209 Ref country code: NO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210309 |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: MK05 Ref document number: 1342718 Country of ref document: AT Kind code of ref document: T Effective date: 20201209 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BG Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210309 Ref country code: LV Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20201209 |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: MP Effective date: 20201209 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20201209 Ref country code: HR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20201209 |
|
REG | Reference to a national code |
Ref country code: LT Ref legal event code: MG9D |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CZ Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20201209 Ref country code: EE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20201209 Ref country code: SM Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20201209 Ref country code: LT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20201209 Ref country code: PT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210409 Ref country code: SK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20201209 Ref country code: RO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20201209 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: PL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20201209 Ref country code: AT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20201209 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R026 Ref document number: 602016049500 Country of ref document: DE |
|
PLBI | Opposition filed |
Free format text: ORIGINAL CODE: 0009260 |
|
PLAX | Notice of opposition and request to file observation + time limit sent |
Free format text: ORIGINAL CODE: EPIDOSNOBS2 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210409 |
|
26 | Opposition filed |
Opponent name: BONE SUPPORT AB Effective date: 20210907 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: AL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20201209 Ref country code: IT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20201209 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20201209 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: ES Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20201209 |
|
PLBB | Reply of patent proprietor to notice(s) of opposition received |
Free format text: ORIGINAL CODE: EPIDOSNOBS3 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20210409 |
|
REG | Reference to a national code |
Ref country code: BE Ref legal event code: MM Effective date: 20211031 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MC Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20201209 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20211004 Ref country code: BE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20211031 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20211004 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: HU Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO Effective date: 20161004 |
|
P01 | Opt-out of the competence of the unified patent court (upc) registered |
Effective date: 20230503 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CY Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20201209 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GB Payment date: 20231018 Year of fee payment: 8 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: SE Payment date: 20231017 Year of fee payment: 8 Ref country code: FR Payment date: 20231016 Year of fee payment: 8 Ref country code: DK Payment date: 20231025 Year of fee payment: 8 Ref country code: DE Payment date: 20231020 Year of fee payment: 8 Ref country code: CH Payment date: 20231102 Year of fee payment: 8 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20201209 |